CN104202985B - Topical compositions comprising fipronil and permethrin and methods of use - Google Patents

Abstract

The subject matter disclosed herein relates to stable, highly effective topical formulations comprising permethrin, fipronil, and a solvent system sufficient to solvate the two active ingredients and limit the degradation of fipronil to its sulfone, and their use in topical applications on animals and the environment. Useful formulations comprise from about 30% to about 55% (w/w) permethrin and from about 2 to 15% (w/w) fipronil and a solvent system comprising N-methylpyrrolidone and a glycol, glycol ether, glycol ester, fatty acid ester, or neutral oil, wherein the N-methylpyrrolidone and glycol, glycol ether, glycol ester, fatty acid ester, or neutral oil are present in a weight to weight ratio of glycol, glycol ether, glycol ester, fatty acid ester, or neutral oil to N-methylpyrrolidone of from about 1:2.0 to about 1:3.5. When combined in the described amounts, these two actives have been found to have unexpectedly enhanced repellent activity against stable flies. However, providing solubility and stability is the formulation described herein, which maintains a synergistic concentration after application to animals.

Description

Topical compositions comprising fipronil and permethrin and methods of use Field of the invention

The subject matter disclosed herein relates to pharmaceutical and veterinary formulations that provide unexpectedly enhanced repellent activity and superior parasiticidal efficacy. The solvent system of the formulation provides excellent solvency over a wide range of conditions and reduces the amount of fipronil sulfone formed.

Cross-references with related applications

This application claims the benefit of priority to U.S. Provisional Patent Application No. 61/602,472, filed February 23, 2012, which is hereby incorporated by reference in its entirety.

Background of the invention

Animals such as mammals and birds are often susceptible to parasite attack. These parasites can be ectoparasites such as fleas, ticks, mosquitoes, mites, flies, sandflies and lice and endogenous parasites such as roundworms, hookworms, flukes and heartworms. The inclusion of livestock makes domesticated animals particularly susceptible to parasitic infection and infestation.

Parasitic diseases can be caused by endoparasites or ectoparasites. Endoparasites refer to those parasites that live inside the host's body (eg, in the stomach, lungs, heart, intestines, etc.). Ectoparasites Those parasites that live on the body of a host but still receive nutrients from the host. Endoparasitic infections can be further classified based on the class of parasite involved in the infection. These parasitic infections and infestation are often associated with disease and death or reduced productivity.

Examples of endogenous parasites that infect animals include, but are not limited to, inter alia Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella ), Capillaria, Toxocara, Toxascaris, Trichuris, Enterobius, Haemonchus, Trichostrongylus ( Trichostrongylus), Ostertagia, Cooperia, Oesophagostomum, Bunostomum, Strongylus, Cyathostomum and Gastrointestinal parasites of the genus Parascaris, and those present in blood vessels or other tissues and organs, including Wuchereria, Brugia, Onchocerca, Parenteral stages of Dirofilaria and Strongyloides, Toxocara and Trichinella.

Ectoparasites that infest humans and domestic animals include arthropods such as ticks, fleas, mites, mosquitoes, lice, etc. and infestation by these parasites can cause the spread of pathogens that can cause serious and even fatal diseases.

Infestation by ectoparasitic arthropods including but not limited to ticks, mites, lice, stable flies, horn flies, blowflies, fall houseflies, fleas, mosquitoes, etc. is also a serious problem. These parasites make the infestation not only cause blood loss and skin damage, but can also interfere with normal eating habits leading to weight loss. Ectoparasitic attack of the host can also cause the spread of pathogens that result in severe disease including, but not limited to, encephalitis, anaplasmosis, babesiosis, Rocky Mountain spotted fever, Lyme disease, ehrlichiosis, West Nile virus, swine pox, malaria, yellow fever, etc., many of them can be fatal to the host. Animals can be infected by several parasites at the same time, since infection by one parasite can debilitate the animal and make it more susceptible to infection by a second parasite.

A prevalent parasite in domesticated animals is the Stable fly (Stomoxys calcitrans) (stable fly). Stable flies feed on the blood of virtually any warm-blooded animal, including humans, companion animals, and livestock. During periods of high stablefly activity, humans can be severely nuisanced and the insect has become known as the biting housefly. A single fly can feed more than once per day. The peak of feeding activity generally occurred during the early morning/am period and again in the afternoon. Stable flies prefer to feed on the lower parts of the host, such as the legs.

Both male and female stable flies feed on blood. Females require a blood meal to produce viable eggs. Females lay their eggs in a variety of decaying animal and plant waste. Stablefly breeds in contaminated wormwood stalk bedding in soaked hay, grasses or forage, piles of moist fermented weed or grass cuttings, spilled green forage, peanut bedding, and seaweed deposits on beaches , sometimes breeding in hay ring feeding sites. Each female fly can lay 500-600 eggs in 4 batches. Eggs hatch into larvae in 2-5 days, which feed and mature in 14-26 days. The average life cycle is 28 days, with a range of 22-58 days, depending on climatic conditions.

Livestock can be severely affected by stable flies. As the flies ingest blood, the animals become debilitated by blood loss and continuous irritation. Stablefly-infested animals such as pigs, cattle, and horses can show reduced body weight gain as well as other deleterious effects. While one stable fly did not cause significant damage, 50-100 of these blood-sucking pests together with 500 horn flies resulted in significant loss of blood. Each year, this can cause significant losses in animal milk and beef production.

Another important parasite is the genus Rhipicephalus, especially those species of Rhipicephalus microscopic (bull tick), Rhipicephalus achromaticus and Rhipicephalus annulus. Ticks such as R. microcephalus are particularly difficult to control because they live in pastures where livestock graze. Other important parasites of cattle and sheep are listed below: myiasis such as Dermatobiahominis (called Berne in Brazil) and Cochliomyia hominivorax (green fly); sheep myiasis such as Lucilia sericata (Lucilia sericata), Lucilia cuprina (called blowfly in Australia, New Zealand and South Africa). These are flies of which the larvae are parasites of animals; dipteran flies, i.e. those whose adults are parasites, such as the western horn fly (Haematobia irritans); lice such as the sheep jaw louse (Linognathus vitulorum) etc.; Pruritus mites (Psoroptes ovis).

More prevalent in domesticated animals such as cats and dogs are the following ectoparasites: cat and dog fleas (Ctenocephalides felis, C. canis, etc.), ticks (Ctenocephalides felis, etc.), Ticks (Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyoma spp., etc.), and mites (Demodex spp., Sarcoptes spp., Cheyletiella spp., Otodectes spp., etc.), lice (Trichodectes spp., Lignothus spp., etc.), mosquitoes ( Aedes spp., Culex spp., Anopheles spp., etc.) and flies (Hematobia spp., Musca spp. , Stomoxys spp., Dermatobia sp., Cochliomyia spp., etc.).

Fleas are a particular problem because they not only adversely affect the health of animals or humans, but also cause a great deal of psychological stress. Furthermore, fleas are vectors of pathogens in animals such as the dog tapeworm (Dipylidium caninum) and in humans.

Similarly, ticks are also detrimental to the physical and psychological health of animals. However, the most serious problem associated with ticks is that they are vectors of pathogens (disease-causing agents) in both humans and animals. Major diseases caused by ticks include borreliosis (Lyme disease caused by Borrelia burgdorferi), babesiosis (or piriplasmosis caused by Babesia sp. ) and rickettsial disease (also known as Rocky Mountain spotted fever). Ticks also release toxins that cause inflammation or paralysis of the host. Sometimes, these toxins are lethal to the host.

Furthermore, mites and lice are particularly difficult to combat, since few active substances act on these parasites and they require frequent treatments.

The above list is not exhaustive and other ectoparasites are well known in the art to be harmful to animals and humans.

While it is known in the art that it is sometimes possible to combine various parasiticides to broaden the spectrum of parasiticides, it cannot be predicted a priori with any reasonable certainty which combinations will work for a particular animal or disease state. For this reason, the results of various combinations are not always successful and there is thus a need in the art for more effective formulations that can be easily administered to animals and have the required solubility, stability and bioavailability.

Formulations comprising different actives are particularly difficult to formulate successfully due to challenges in achieving the required solubility, stability and bioavailability. Thus, there is a need in the art for combination antiparasitic formulations that meet the required solubility, stability and bioavailability of the parasiticides formulated therein.

Summary of the invention

The subject matter disclosed herein relates to stable, highly effective topical formulations comprising a pyrethroid such as permethrin, an N-arylpyrazole such as fipronil, and Frenilil sulfone is safe for use in solvent systems for topical application. In one embodiment, the topical formulation is in the form of a paint formulation. In yet another embodiment, the topical formulation is in the form of a pour-on formulation. In one embodiment, the formulation comprises about 30 to about 55% (w/w) permethrin and about 2 to 15% (w/w) fipronil and a solvent system comprising N-methylpyrrolidone (NMP) and glycols, glycol ethers, glycol esters, fatty acid esters or neutral oils. In certain embodiments, formulations of the present invention comprise at least about 40% (w/w) permethrin and at least about 5% (w/w) fipronil in a solvent system comprising NMP and di Alcohol, glycol ether, glycol ester, fatty acid ester or neutral oil, wherein NMP and glycol, glycol ether, glycol ester, fatty acid ester or neutral oil are in the ratio of about 1:2.0 to about 1:3.5 ( Glycols, Glycol Ethers, Glycol Esters, Fatty Acid Esters or Neutral Oils:NMP ratios are present. In other embodiments, the ratio of glycol, glycol ether, glycol ester, fatty acid ester, or neutral oil to NMP is from about 1:2.0 to about 1:3.0, from about 1:2.5 to about 1:3.5, or About 1:2.5 to about 1:3.0 (weight: weight).

These two actives have been found to have excellent parasiticidal activity and unexpectedly enhanced repellency of stable flies when combined in the amounts described in the solvents described herein. However, it is the specific combination of solvents in the formulations described herein that provides the required solvency and physical stability and limits the oxidation of fipronil to its sulfone, which maintains the concentration of the active after administration to animals, causing unexpected Unexpected enhanced repellency and excellent efficacy against stable flies. Additionally, as described herein, the choice of diluent to be combined with NMP is critical to limiting fipronil oxidation of fipronil sulfone and maintaining effective concentrations in the formulation.

In certain embodiments of the invention, additional active agents may be combined in topical formulations comprising fipronil and permethrin. Additional active agents include, but are not limited to, avermectin, milbemycin, spinosyn, spinosoids, benzimidazoles, thiazide, pyrantel , thienylhydropyrimidine, praziquantel, closantel, closulon, aminoacetonitrile active agent, insect growth regulator, neonicotinoid or arylpyrrol-2-ylcyanoethylamino active agent, or a combination thereof.

The subject matter disclosed herein also relates to methods of combating infestation by ectoparasites, including but not limited to fleas, ticks, mosquitoes, and various species, with formulations on or around mammals or birds and in their habitats. A type of parasitic fly such as the stable fly. The method comprises administering to the mammal or bird an effective amount of a formulation described herein, especially a paint or pour-on formulation. Animals include mammals such as dogs, zebras and horses, cattle, pigs, yaks, rodents, deer, goats, sheep and llamas and birds such as chickens, turkeys and quail. The environment includes animal housing such as dog bedding, stables and chicken litter.

The subject matter of the present application also relates to methods of preparing the compositions described herein. The method comprises contacting one or both of the active substances with a solvent selected from one or more of N-methylpyrrolidone and glycols, glycol ethers, glycol esters, fatty acid esters or neutral oils , wherein the final formulation contains N-methylpyrrolidone and a glycol, glycol ether, glycol ester, fatty acid ester or neutral oil. In one embodiment, glycol, glycol ether, glycol ester, fatty acid ester or neutral oil and NMP are in the ratio of about 1:2.0 to about 1:3.5, about 1:2.0 to about 1:3.0, about 1 :2.5 to about 1:3.5, or about 1:2.5 to about 1:3.0 (weight:weight) combination of ratios of glycols, glycol ethers, glycol esters, fatty acid esters, or neutral oil:NMP. The formulations described herein are stable and exhibit unexpectedly enhanced repellency and efficacy against stable flies.

Description of drawings

The following detailed description is provided by way of example, and is not intended to limit the invention to the particular embodiments described, which are best understood in conjunction with the accompanying drawings, in which:

Figure 1 depicts a mixture containing N-methylpyrrolidone (NMP) and diethylene glycol monoethyl ether (DGME, )or Formulation of 812 (neutral oil) at sulfone formation at 50°C. The data show that the DGME-containing formulations contained greater than 10% higher fipronil sulfone concentrations than the neutral oil-containing formulations. Each formulation contained about 6% (w/w) fipronil, 45% (w/w) permethrin and 33% (w/w) NMP. Formulation A contained (DGME), made up to 100% (~14-15% w/w); formulation B contained 812, make up to 100% (-14-15% w/w). The formulations contained no added antioxidants in this study.

Figure 2 depicts the formulations, all of which contain 812 and no antioxidants or different levels of antioxidants. The data show that all formulations have fipronil sulfone levels below about 2.950%. The formulation containing 0.10% BHT had a fipronil sulfone level of about 2.800%.

Figure 3 depicts the presence of fipronil/permethrin and NMP/DGME or NMP/ 812 formulation for sandfly repellency.

Figure 4 depicts a drug containing fipronil/permethrin and NMP/DGME, 812 Efficacy of formulations of either N,N-dimethyldecylamide (DMDA)/butyl CELLOSOLVE ^™ acetate (BCA), or permethrin alone, against fleas. NMP/DGME formulations were more susceptible to fipronil degradation.

Figure 5 depicts a mixture containing fipronil/permethrin and NMP/DGME, NMP/ Efficacy of formulations of 812 or DMDA/BCA, or permethrin alone, against ticks.

Figure 6 depicts the efficacy of formulations containing permethrin alone or fipronil/permethrin on rats against stable flies.

Figure 7 depicts stable fly repellency in rats of formulations containing permethrin alone or fipronil/permethrin.

Figure 8 depicts stable fly repellency of formulations comprising fipronil and permethrin on dogs one hour after exposure.

Figure 9 depicts the efficacy of formulations comprising fipronil and permethrin against stable flies in dogs one hour after exposure.

Figure 10 depicts the repellency of formulations comprising fipronil and permethrin against Culexpiens one hour after exposure.

Detailed description of the invention

The subject matter disclosed in this application is described in more detail below. However, many modifications and other implementations of the subject matter disclosed herein will be apparent to one skilled in the art to which the subject matter disclosed herein has reference to the foregoing teachings of this application. Therefore, it is to be understood that the subject matter disclosed herein is not to be limited to the particular embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims.

It is well known that formulating actives as a paint or pour-on formulation is challenging. Even more challenging is the successful formulation of two different actives into a composition where both remain in solution and are available in the desired amounts. Since the combination has been shown herein to have unexpectedly enhanced repellency against stable flies, it is critical that the formulations provide the required solubility and physical and chemical stability to ensure concentrations that cause enhanced repellence even after the formulations are administered to animals be maintained.

Disclosed herein are unique combinations of solvent systems for use with combinations of permethrin and fipronil, wherein the formulation components are present in specified ranges and specific ratios relative to each other. The enumerated ratios are not broadly generalized quantities, but specific values for the effective ranges and ratios of fipronil and permethrin. Advantageously, the solvent systems described herein solvate high concentrations of permethrin and are compatible with fipronil. Thus, the active remains in solution, does not substantially degrade and can combat pest infestation at concentrations effective where infestation can occur. As used herein, the terms "physical stability" and "physically stable" refer to formulation properties wherein no significant amounts of permethrin or fipronil crystals form at low temperatures (including -20°C, 4°C, and 10°C), The active ingredient remains in solution even after application. The physical stability of a composition can be described as crystal formation over a period of days, weeks, months or even years when the formulation is stored at a particular temperature. The solvent system also provides the safety features required for its intended use.

Formulations containing permethrin and additional active ingredients are often physically unstable. Permethrin, especially at high concentrations above 20% (w/w), tends to form crystals in formulations. Where a second active is added to the formulation, the problem of physical instability can increase exponentially since the physical properties and requirements of formulating additional ingredients must also be considered. The second preferred active disclosed herein is fipronil. However, in the case of fipronil combined with N-methylpyrrolidone (NMP), an effective solvent for high concentrations of permethrin, significant levels of oxidation of fipronil to fipronil sulfone were observed.

Fipronil sulfone is also the major in vivo metabolite of fipronil. It has the following structure:

The fipronil used to make the formulation can be formulated with fipronil sulfone. In other words, it is possible that useful grades of fipronil have a certain amount of fipronil sulfone already present as a by-product of its manufacture. In one embodiment, fipronil has below about 3.5% fipronil sulfone when formulated with NMP. Certain grades of fipronil may have lower levels or even 0% fipronil sulfone. However, once fipronil is in contact with NMP, it is believed that fipronil sulfone can continue to form in solution. Furthermore, the cost of using fipronil which is completely free of fipronil sulfone is significantly higher. However, compared to formulations with other typical solvents used in topical compositions, the formulations described herein advantageously minimize or substantially slow further fipronil sulfone formation, regardless of how much is present at the time of formulation.

The solvent system described here was designed after the discovery that fipronil was susceptible to fipronil sulfone formation in the presence of NMP. While not being bound by any particular theory, it is believed that the peroxide present in the NMP promotes the formation of fipronil sulfone. In addition, NMP is known to be able to generate peroxides in the presence of oxygen (see Drago and Riley, J. Am. Chem. Soc. 1990, 112, 215-218; Reynolds et al., Journal of Pharmaceutical Sciences, 2012, 101(2) , pp.761-776). Thus, it has been found that while NMP is a useful solvent, it presents a technical obstacle when used as a solvent for fipronil in concentrated topical formulations such as paint formulations. Oxidation of fipronil in NMP must be addressed because NMP is an effective solvent for permethrin at the concentration levels present in the formulations disclosed herein. However, it was unexpectedly observed that the NMP requirement in the formulations of the invention resulted in higher than desired levels of oxidation of fipronil to fipronil sulfone.

N-methylpyrrolidone (NMP) is a compound having a 5-membered lactam structure. It is a clear to slightly yellowish liquid soluble in water and common organic solvents. It is a polar aprotic solvent and a very weak base. Other names for this compound are: 1-methyl-2-pyrrolidone, N-methyl-2-pyrrolidone, and m-pyrrole, and Although useful, its use in topical application can cause problems for the experienced formulator. In some cases, NMP can cause skin irritation, redness, or dermatitis. Accordingly, while acceptable in topical formulations, it is preferred that the levels be as low as possible.

Traditional solvents used in NMP in combination with fipronil in topical formulations such as diethylene glycol monoethyl ether ( or DGME) oxidation of fipronil to fipronil sulfone was observed at higher than expected levels. Diethylene glycol monoethyl ether is commonly used in many topical formulations and has been found to be a very effective solvent for formulating topical fipronil formulations. When DGME and other diluents are used in combination with NMP, the amount of NMP can be reduced, provided the necessary physical properties of the composition remain the same. However, it has been found that when NMP is combined with a co-solvent commonly used with fipronil, such as DGME, fipronil is oxidized to its sulfone in higher than desired amounts. Thus, to minimize the formation of fipronil sulfone, antioxidants were used at levels approximately 10 times the effective antioxidant levels required in the formulations described herein.

It has been surprisingly found that, compared to other solvents typically used in topical formulations of fipronil, NMP containing and in combination with The neutral oil solvent system of 812 (caprylic/capric triglyceride) resulted in significantly lower sulfone formation. Neutral oils are known in the art. They are light to colorless liquids with a neutral odor and taste.

-Type Neutral oils are clear, slightly yellowish esters of caprylic and capric fatty acids and glycerol or propylene glycol derived from saturated coconut and palm kernel oils. Certain neutral oils are triglycerides of graded vegetable fatty acids with chain lengths _C8 to _C10 . Two commercially available products are called 810 and 812. Yet another useful neutral oil is a triglyceride of graded vegetable fatty acids of chain length _C8 and _C10 combined with linoleic acid (about 4-5%). Commercially available products are called 818. Yet another useful neutral oil is the glycerides of chain length _C8 and _C10 graded vegetable fatty acids and succinic acid in combination. Commercially available products are called 829. Yet another useful neutral oil is the propylene glycol diester of chain length _C8 and _C10 saturated vegetable fatty acids in combination with succinic acid. Commercially available products are called 840 (Propylene Glycol Dicaprylate/Dicaprate). Other fatty acids include stearyl stearate, stearyl palmitate and stearyl myristate. Other examples of suitable neutral oils and fatty acid esters include hydrocarbon-containing vegetable oils, such as liquid triglycerides of fatty acids containing from 4 to 24 carbon atoms (such as triglycerides, heptanoic acid and caprylic acid), sunflower oil, corn oil , soybean oil, gourd oil, grapeseed oil, sesame oil, hazelnut oil, almond oil, macadamia nut oil, castor oil, avocado oil, jojoba oil, and shea butter; synthetic esters, such as synthetic fatty acid esters, such as purcellin Oil, Isononyl Isononanoate, Isopropyl Myristate, 2-Ethylhexyl Palmitate, 2-Octyldodecyl Stearate, 2-Octyldodecyl Erucate and isostearyl isostearate. As detailed herein, the requirement for the diluent is that it introduces substantially no additional peroxide species into the NMP/co-solvent system. Thus, fipronil sulfone formation is moderated and substantially lower levels of antioxidants can be used to create long-term stability of permethrin, fipronil combination formulations.

The fipronil/permethrin compositions described herein containing NMP in combination with a neutral oil will have significantly lower production of fipronil sulfone. Usefully, the compositions of the present application inhibit fipronil sulfone formation such that the level of fipronil sulfone does not increase about 3 months after formulation by more than the initial fipronil sulfone present at the time of formulation (e.g. pure fipronil starting material about 50% of the amount present in ), the level/amount being the area % of the fipronil sulfone peak relative to the fipronil peak as measured by HPLC. In one embodiment, the solvent system of the present invention inhibits the formation of fipronil sulfone to such an extent that 3 months after formulation, fipronil sulfone does not increase by more than about 45%; or fipronil sulfone does not increase by more than about 40% of the initial fipronil sulfone present at the time of formulation; or fipronil sulfone does not increase by more than about 35% of the initial fipronil sulfone present at the time of formulation or fipronil sulfone does not increase by more than about 30% of the initial fipronil sulfone present at the time of formulation; or fipronil sulfone does not increase by more than about 25% of the initial fipronil sulfone present at the time of formulation. In yet another embodiment, 3 months after formulation, fipronil sulfone does not increase by more than about 20% of the initial fipronil sulfone present at the time of formulation; or fipronil sulfone does not increase by more than About 15% of the initial fipronil sulfone. In yet another embodiment, 3 months after formulation, the fipronil sulfone does not increase by more than about 10% of the initial fipronil sulfone present at the time of formulation.

The purpose of the antioxidants in the composition is generally to combat any peroxides present in the NMP. It has been found that with careful selection of the diluent to limit the additional introduction of harmful oxidative species such as peroxide species into the composition, the amount of antioxidant can preferably be kept at GRAS (generally regarded as safe) levels or substantially lower. In certain embodiments, the effective amount of antioxidant is no greater than about 0.25% (w/w). In yet another embodiment, the antioxidant is present in an amount not greater than about: 0.2% (w/w); 0.19% (w/w); 0.18% (w/w); 0.17% (w/w); 0.16% (w 0.15% (w/w); 0.14% (w/w); 0.13% (w/w); 0.12% (w/w) or 0.11% (w/w). In yet another embodiment, the antioxidant is present at a concentration of not greater than about 0.1% (w/w).

A further problem with concentrated topical formulations is that any amount of crystals in the formulation can result in the active being concentrated in the precipitated material at concentrations too high for safe, point-of-application topical use. Furthermore, since precipitation effectively removes active from solution, the concentration of active remaining in solution may be too low to provide the efficacy described herein. Additionally, once crystals start to form, they become seeds for further crystal formation. This process leads to increased precipitation of components from the solvent system, and detrimental effects on the active concentration in the formulation.

It will be apparent that the relative amounts of the actives will be altered if one or both of the actives form crystals or precipitate from solution before or after administration. Accordingly, it would be desirable for the amount of active to deviate from that required for enhanced repellant activity. Thus, the property of the individual actives of the compositions of the present application to remain in solution even after application to animals contributes to the observed enhanced activity against stable flies. As reported in WO2007/143298, which is hereby incorporated in its entirety, it is difficult to form high concentration solutions of permethrin. However, the compositions of the present application comprise a minimum concentration of permethrin of about 30% (w/w), and in certain embodiments about 40 to about 45% (w/w) of permethrin. The difficulty of successfully formulating permethrin at these concentrations increases exponentially in the case of formulating a second, different active. This is especially true if the actives have different physical properties. Surprisingly, the compositions described herein have been shown to exhibit unexpectedly enhanced repellency and superior insecticidal efficacy against stable flies when applied to a topical area on an animal. Thus, the observed enhanced repellence would be expected to result from each active concentration as the composition spreads over the animal's coat and skin. The unexpectedly enhanced repellence is not limited to the site where the composition is applied directly to the animal, and is important for effective control of stable flies and other ectoparasites, since these ectoparasites will eating in different positions. The formulations described herein, even as the composition is transferred on the animal, provide an effective amount of the active agent of the composition.

Although many solvent systems exist, it is impossible for the formulator in the art to predict which system will be effective for a given combination of active ingredients. However, the presently described solvent system addresses the problem of formulating fipronil and permethrin together in effective amounts that result in unexpectedly enhanced repellence of certain parasitic flies, including stable flies, wherein fluoride that causes enhanced repellency Effective concentrations of chlorpronil and permethrin were maintained.

Fipronil (5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole) is 1-N- Arylpyrazole insecticide. It has the following structure:

It is a member of a class of chemicals well known in the art and their use in the control of parasites in mammals such as domesticated livestock or companion animals or birds, alone or in combination with other pesticides such as insect growth regulators , said parasites include insect pests such as fleas, stable flies, horn flies or mosquitoes, and mite pests such as ticks, mites and lice. See for example EP-A-295,217, EP295177, EP-A-840-686, EP-A-352,944, WO00/35844, WO98/39972, U.S. Patent Nos. , 6,090,751 and 6,096,329. These references are incorporated herein in their entirety. The families of compounds defined in these patents are extremely active. Fipronil is particularly effective against fleas and ticks, but not exclusively. However, fipronil is not known to have any repellant activity against ectoparasites.

Permethrin is a member of the pyrethroid class. It has the following structure:

A class of synthetically derived insecticides known as pyrethroids. These compounds are particularly effective against mosquitoes (Culex spp.) that transmit West Nile virus. Pyrethroids are structurally related to the natural pyrethrins, pyrethrin I and pyrethrin II. Synthetic pyrethroids include permethrin (U.S. Patent No. 4,113,968), resmethrin, and sumithrin (U.S. Patent Nos. 3,934,023 and 2,348,930). The repellent efficacy of permethrin against various arthropods is well known. These references are incorporated herein in their entirety.

Combinations of fipronil and a pyrethroid such as permethrin are known (in particular, EPA Registration Submissions on PDMS searchable database; Submitter Name: Virbac AH, Inc.). by trade name The product for sale was approved in the United States on November 18, 2011. The Material Safety Data Sheet (MSDS) for this product states that it contains fipronil, permethrin and diethylene glycol monoethyl ether. WO2001/065941A1 and EP1013170A1 propose combinations of N-arylpyrazoles and pyrethroids for application against plant pests. JP11049618A2 uses a similar mixture to prevent ingestion damage on timber construction. WO95/22902A1 uses the mixture for direct control of termites. GB2396557A1 teaches that it is possible to treat ectoparasites with a mixture of N-arylpyrazoles and pyrethroids (if appropriate also adding synergists such as MGK264 or butanobuterol) when using concentrated powder formulations. These references are incorporated herein in their entirety.

However, critical for the active to function is the use of a solvent system that provides the necessary solubility and chemical and physical stability to ensure the effective concentration responsible for enhanced repellant efficacy after administration and until the active effectively coats the animal or reaches The infected sites are maintained in solution. There have been no reports of the formulation components required to successfully formulate a combination of fipronil and permethrin, where permethrin is present in high concentrations in a paint or pour-on formulation, in various Concentrations are maintained under conditions that result in enhanced repellence of certain ectoparasites including, but not limited to, stable flies. Even formulators skilled in the art cannot predict with reasonable certainty which combinations and solvents will ultimately work together.

In one embodiment, the subject of the present application relates to a formulation comprising permethrin at a concentration of about 30% w/w to about 55% w/w; fluorine at a concentration of about 2% w/w to about 15% w/w chlornil; and a) one or more neutral oils and b) N-methylpyrrolidone (NMP).

In yet another embodiment, the present invention provides formulations comprising permethrin at a concentration of about 30% w/w to about 55% w/w; fluoride at a concentration of about 2% w/w to about 15% w/w Nitrile; and a) one or more neutral oils and b) NMP, wherein a) one or more neutral oils and b) NMP are neutralized in one or more of about 1:18 to about 1:2.8 The oil:NMP weight:weight ratio exists. In this embodiment, if an antioxidant is present, it may be present at a concentration of not greater than about 0.25% (w/w).

In yet another embodiment, the present invention provides formulations comprising permethrin at a concentration of about 30% w/w to about 55% w/w; fluoride at a concentration of about 2% w/w to about 15% w/w Nitrile; and a) one or more neutral oils and b) NMP, wherein a) one or more neutral oils and b) NMP are neutralized with one or more of about 1:2.0 to about 1:3.5 The oil:NMP weight:weight ratio exists. In this embodiment, if an antioxidant is present, it may be present at a concentration of not greater than about 0.25% (w/w).

In one embodiment, the present invention provides a formulation comprising permethrin at a concentration of at least about 40% w/w; fipronil at a concentration of at least about 5% w/w; and a) one or more neutral Oil and b) NMP, wherein a) one or more neutral oils and b) NMP at about 1:1.18 to about 1:2.8 or about 1:2.0 to about 1:3.5 of one or more neutral oils The weight:weight ratio of :NMP exists. In this embodiment, if an antioxidant is present, it may be present at a concentration of not greater than about 0.25% (w/w).

In yet another embodiment, the present invention provides a formulation comprising permethrin at a concentration of at least about 40% w/w; fipronil at a concentration of at least about 5% w/w; and a) one or more neutral Oil and b) NMP, wherein a) one or more neutral oils and b) NMP are present in a ratio of one or more neutral oils:NMP from about 1:2.5 to about 1:3.5. In this embodiment, if an antioxidant is present, it may be present at a concentration of not greater than about 0.25% (w/w).

In yet another embodiment, the present invention provides formulations comprising permethrin at a concentration of about 40% w/w to about 55% w/w; fluoride at a concentration of about 5% w/w to about 15% w/w Nitrile; and a) one or more neutral oils and b) NMP, wherein a) one or more neutral oils and b) NMP are in the ratio of about 1:1.8 to about 1:2.8 or about 1:2.0 to about A weight:weight ratio of one or more neutral oils:NMP of 1:3.5 is present. In this embodiment, if an antioxidant is present, it may be present at a concentration of not greater than about 0.25% (w/w).

In yet another embodiment, the present invention provides formulations comprising permethrin at a concentration of about 40% w/w to about 55% w/w; fluoride at a concentration of about 5% w/w to about 15% w/w Nitrile; and a) one or more neutral oils and b) NMP, wherein a) one or more neutral oils and b) NMP are neutralized in one or more of about 1:2.5 to about 1:3.5 The oil:NMP ratio exists. In this embodiment, if an antioxidant is present, it may be present at a concentration of not greater than about 0.25% (w/w).

In yet another embodiment, the present invention provides formulations comprising permethrin at a concentration of about 40% w/w to about 50% w/w; fluoride at a concentration of about 5% w/w to about 10% w/w Nitrile; and a) one or more neutral oils and b) NMP, wherein a) one or more neutral oils and b) NMP are neutralized with one or more of about 1:2.5 to about 1:3.0 The oil:NMP ratio exists. In this embodiment, if an antioxidant is present, it may be present at a concentration of not greater than about 0.25% (w/w).

In one embodiment of the invention, the level of fipronil sulfone in a composition described herein is less than about 3 months after formulation, relative to the peak area of fipronil, as measured by high pressure liquid chromatography (HPLC). 6% area. In other embodiments, the level of fipronil sulfone is less than about 5% at about 3 months after formulation or less than about 4% at about 3 months after formulation. In other embodiments, the level of fipronil sulfone is less than about 3.5% about 3 months after preparation of the formulation. In yet another embodiment, the level of fipronil sulfone is less than about 3.2% at about 3 months of formulation, less than about 3.1% at about 3 months of formulation, less than about 3.0% at about 3 months of formulation, and about Less than about 2.9% at 3 months or less than about 2.8% at about 3 months as formulated. In other embodiments, the level of fipronil sulfone is less than about 2.7% at about 3 months after formulation, less than about 2.6% at about 3 months after formulation, or less than about 2.5% at about 3 months after formulation. In other embodiments, the level of fipronil sulfone is less than about 2.4% at about 3 months after formulation, less than about 2.3% at about 3 months after formulation, and less than about 2.2% at about 3 months after formulation. In yet another embodiment, the level of fipronil sulfone is less than about 2.1% at about 3 months after formulation or less than about 2.0% at about 3 months after formulation. As used herein, "about 3 months after formulation" means a period of 10 to 14 weeks from when fipronil comes into contact with other components in the formulation. Generally, it is the time from the contact of fipronil with NMP. The level of fipronil sulfone relative to the peak area of fipronil in the samples was measured by HPLC.

The ratio of one or more neutral oils:NMP provides the unique stability of the two active ingredients permethrin and fipronil in the formulation of the present application, especially since the one or more neutral oils are chosen so as not to Significant amounts of peroxide species are introduced. Unlike other formulations known in the art for different actives, the formulations disclosed herein are capable of solvating permethrin and inhibiting or preventing its crystallization, and also limit the formation of fipronil sulfone in solution. Thus, both active ingredients are present at the desired concentrations, which are shown herein to have unexpectedly enhanced efficacy against stable flies.

A useful concentration of fipronil in the composition is from about 2% (w/w) to about 15% (w/w). In one embodiment, fipronil is present at a concentration of about 3% (w/w) to about 10% (w/w). In yet another embodiment, fipronil is present at a concentration of about 4% (w/w) to about 8% (w/w). In yet another embodiment fipronil is present at a concentration of about 6% (w/w).

Useful concentrations of permethrin in the compositions of the present invention are from about 35% (w/w) to about 50% (w/w). In one embodiment, permethrin is present at a concentration of about 40% (w/w) to about 48% (w/w). In yet another embodiment, permethrin is present at a concentration of about 42% (w/w) to about 47% (w/w). In yet another embodiment, permethrin is present at a concentration of about 45% (w/w).

In certain embodiments, the present invention provides the following formulations: Formulation A) Fipronil is about 6% (w/w); Permethrin is about 45% (w/w); NMP is about 35% (w/w); DGME (diethylene glycol monoethyl ether or ) about 10-15% (w/w) and about 0.1% (w/w) of BHT; formulation B) fipronil about 6% (w/w); permethrin about 45% (w/w) w); NMP is about 35% (w/w); enough to complete the amount of formulation (QS) 812 is about 10-15% (w/w) and about 0.1% (w/w) BHT. In certain embodiments, the amount of DGME in formulation A) is about 12-14%, about 12% (w/w), about 13% (w/w) or about 14% (w/w). In other embodiments, in formulation B) The amount is about 12% (w/w), about 13% (w/w) or about 14% (w/w).

Dosages of actives can be readily determined by those skilled in the art. In general, however, a dose of about 0.001 to about 100 mg per kg body weight, more typically about 0.01 mg to about 50 mg/kg body weight, given as a single administration or in divided doses for a period of 1 to 5 days may be desirable. Satisfactory, but there may of course be instances where higher or lower dosage ranges are indicated and this is within the scope of the particular dosing period for the particular case. It will be appreciated that the dosage volume of the formulation can also be determined and then adjusted as desired.

In certain embodiments, the composition comprises about 6.0% (w/w) fipronil and about 45% (w/w) permethrin. The composition also comprises N-methylpyrrolidone and the neutral oil solvent system described herein.

The one or more neutral oil and N-methylpyrrolidone components can be quantified in terms of their respective relative amounts. In certain embodiments, a useful weight:weight ratio of one or more neutral oils:NMP is 1:1.8 to about 1:3.5; or about 1:2.0 to about 1:3.5. In other embodiments, the ratios include from about 1:1.9 to about 1:2.7; from about 1:2.0 to about 1:3.0; and from about 1:2.5 to about 1:3.0 of one or more neutral oils:NMP. In other embodiments, ratio values include: 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.1, 1:3.2, 1:3.3, 1:3.4 and 1:3.5 of one or more neutral oils: NMP. In other embodiments, the ratio comprises one or more neutral oils:NMP from about 1:2.2 to about 1:2.4. In yet another embodiment, the ratio is from about 1:2.3 to about 1:3.0 of one or more neutral oils:NMP. These ratios are relative amounts, but are suitably based on the useful amount of one or more neutral oils or NMP.

A useful concentration of NMP in the composition is from about 25% (w/w) to about 44% (w/w). In one embodiment, the concentration of NMP is from about 28% (w/w) to about 42% (w/w) or from about 31% (w/w) to about 39% (w/w). In other embodiments, the concentration of NMP is 33% (w/w) to about 37% (w/w). In yet another embodiment, NMP is present at a concentration of about 35% (w/w). From the level of NMP present or expected, the corresponding amount of diluent can be calculated.

The composition contains an amount of neutral oil which minimizes the formation of fipronil sulfone in formulations comprising fipronil and NMP. The amount of neutral oil used in the formulation can vary slightly since it is used in an amount to make up the formulation (QS). Useful concentrations of one or more neutral oils in the compositions of the present invention include, but are not limited to, from about 11% (w/w) to about 18% (w/w). In certain embodiments, the concentration of one or more neutral oils includes about 12% (w/w) to about 17% (w/w) and about 13% (w/w) to about 16% (w/ w). In other embodiments, one or more neutral oils are present at about 12% (w/w) to about 14% (w/w), about 13% (w/w) to about 15% (w/w) concentration exists. In yet another embodiment, the neutral oil is present at a concentration of about 14% (w/w).

When present in preferred embodiments, the antioxidant is beneficially present at a concentration of no greater than about 0.25% (w/w), although higher concentrations can be added. In certain embodiments, the concentration is no greater than about: 0.2% (w/w); 0.19% (w/w); 0.18% (w/w); 0.17% (w/w); 0.16% (w/w ); 0.15% (w/w); 0.14% (w/w); 0.13% (w/w); 0.12% (w/w) or 0.11% (w/w). In yet another embodiment, if present, the antioxidant is present at a concentration of no greater than about 0.1% (w/w). Suitable inorganic antioxidants are, for example, sulfites and hydrogensulfites, especially sodium hydrogensulfite. In one embodiment, the antioxidant is a phenolic antioxidant such as anisole, butylated hydroxytoluene, and butylated hydroxyanisole, and mixtures thereof with each other. In other embodiments, the antioxidants are those conventional in the art and include, for example, ascorbic acid, sodium metabisulfite, propyl gallate, sodium thiosulfate, or mixtures of no more than two thereof. When used in formulations containing NMP and diluents that do not significantly add peroxide species to the formulation, the amount of antioxidant can advantageously be kept substantially less than that in formulations that do not contain the beneficial solvent system of the present invention. required amount.

In other embodiments, the subject matter of the present application relates to a pesticide composition exhibiting surprising and unexpected repellence of parasites including stable flies, comprising about 2% (w/w) to about 15% (w/ w) fipronil; about 30% (w/w) to about 55% (w/w) permethrin; glycols, glycol ethers, glycol esters or fatty acid esters and N-methylpyrrolidone, wherein Said glycol, glycol ether, glycol ester or fatty acid ester and N-methylpyrrolidone at about 1:1.8 to about 1:2.8, about 1:2.0 to about 1:3.5, about 1:2.0 to about 1: 3.0, from about 1:2.5 to about 1:3.5 or from about 1:2.5 to about 1:3.0 in a weight:weight ratio; and optionally an antioxidant.

In yet another embodiment, the subject of the present application relates to a pesticide composition comprising at least about 5% (w/w) fipronil; at least about 40% (w/w) permethrin; glycols, glycol ethers, diols, Alcohol ester or fatty acid ester and N-methylpyrrolidone, wherein said glycol, glycol ether, glycol ester or fatty acid ester and N-methylpyrrolidone with about 1:2.0 to about 1:3.5, about 1: 2.0 to about 1:3.0, about 1:2.5 to about 1:3.5, or a weight:weight ratio of about 1:2.5 to about 1:3.0 exists; and optionally an antioxidant, wherein the composition provides an unexpected enhancement repellence of parasitic flies including stable flies.

In yet another embodiment, the subject of the present application relates to a pesticide composition comprising about 5% (w/w) to about 15% (w/w) fipronil; about 40% (w/w) to about 55% ( w/w) permethrin; glycol, glycol ether, glycol ester or fatty acid ester and N-methylpyrrolidone, wherein the glycol, glycol ether, glycol ester or fatty acid ester and N-methylpyrrolidone an oxypyrrolidone is present in a ratio of about 1:2.0 to about 1:3.5; and optionally an antioxidant.

In yet another embodiment, the subject matter of the present application relates to a pesticide composition comprising about 5% (w/w) to about 10% (w/w) fipronil; about 40% (w/w) to about 50% ( w/w) permethrin; glycol, glycol ether, glycol ester or fatty acid ester and N-methylpyrrolidone, wherein the glycol, glycol ether, glycol ester or fatty acid ester and N-methylpyrrolidone an oxypyrrolidone is present in a ratio of about 1:2.0 to about 1:3.5; and optionally an antioxidant.

In yet another embodiment, the subject of the present application relates to a pesticide composition comprising about 6% (w/w) (w/w) fipronil; about 45% (w/w) permethrin; diol, diol Ether, glycol ester or fatty acid ester and N-methylpyrrolidone, wherein said glycol, glycol ether, glycol ester or fatty acid ester and N-methylpyrrolidone are in a ratio of about 1:2.0 to about 1:3.5 ratio present; and optionally an antioxidant.

Useful amounts of permethrin and fipronil in these formulations are as described above. In certain embodiments, the formulations described above provide unexpectedly enhanced repellence of parasitic flies, including stable flies, and superior insecticidal efficacy.

In these embodiments, the antioxidant may be present at a concentration of about 0.005 to about 1% (w/w), or about 0.01 to about 0.05% (w/w). In certain embodiments, the antioxidant may be present at a concentration of about 0.01 to about 1% by weight, or about 0.05% to about 0.5% by weight. In yet another embodiment, the antioxidant is present at a concentration of about 0.075 to about 0.2% by weight. Amounts below 0.2% by weight are also useful depending on the diluent chosen or the level of peroxide in the NMP.

Glycols useful in the composition include diethylene glycol, polyethylene glycol (PEG, including all low to high molecular weight PEGs), propylene glycol and polypropylene glycol. Glycol ethers include but not limited to methyl diglycol, ethyl diglycol, propyl diglycol, butyl diglycol, methyl glycol, ethyl glycol, ethylene glycol monomethyl ether , diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, propylene glycol monomethyl ether and tetrahydrofurfuryl alcohol polyglycol ether (tetraethylene glycol or tetrahydrofuran polyglycol ether (glycofurol)). In one embodiment, the glycol ether is diethylene glycol monoethyl ether. Glycol esters that may be used in the formulation include carboxylic acid esters of glycols or glycol ethers, including but not limited to acetates of glycols and glycol ethers such as ethylene glycol monoethyl ether acetate (ethyl CELLOSOLVE ^TM Acetate), Ethylene Glycol Monobutyl Ether Acetate (Butyl CELLOSOLVE ^TM Acetate), Ethylene Glycol Monomethyl Ether Acetate, etc.

In the above embodiments comprising glycols, glycol ethers, glycol esters or fatty acid esters and NMP, the concentration of NMP in the compositions of the present invention may be from about 25% (w/w) to about 44% (w/w w). In other embodiments, NMP may be present at a concentration of about 28% (w/w) to about 42% (w/w), or about 31% (w/w) to about 39% (w/w). In other embodiments, NMP may be present at a concentration of about 33% (w/w) to about 37% (w/w). In yet another embodiment, NMP may be present at a concentration of about 35% (w/w). From the NMP levels present or desired, the corresponding amount of diluent can be calculated.

The glycol, glycol ether, glycol ester or fatty acid ester and N-methylpyrrolidone components can be quantified in terms of their respective relative amounts. Useful weight:weight ratios of glycols, glycol ethers, glycol esters, or fatty acid esters to NMP include ratios of 1:2.0 to about 1:3.5. In other embodiments, the ratios include about 1:1.18 to about 1:1.28, about 1:2.0 to about 1:3.0; about 1:1.9 to about 1:2.7; about 1:2.0 to about 1:2.6; and about 1 :2.5 to about 1:3.0 of glycol, glycol ether or fatty acid ester:NMP. In other embodiments, the weight:weight ratio of glycol, glycol ether or fatty acid ester:NMP is 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.4, 1:2.5, 1:2. 2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.1, 1:3.2, 1:3.3, 1:3.4 or 1:3.5. In other embodiments of the invention, the weight:weight ratio of glycol, glycol ether, glycol ester or fatty acid ester:NMP is from about 1:2.5 to about 1:3.0 or from about 1:2.5 to about 1:3.5 . These ratios are relative amounts, but are suitably based on the useful amount of glycol, glycol ether or fatty acid ester or NMP.

In certain embodiments, the composition contains an amount of a glycol, glycol ether, glycol ester, or fatty acid ester that minimizes fipronil sulfone formation in formulations comprising fipronil and NMP. Generally, the amount of glycol, glycol ether, glycol ester or fatty acid ester used in the formulation is a quantity sufficient to complete the formulation (QS) and varies slightly thereby. Useful concentrations of glycols, glycol ethers, glycol esters or fatty acid esters include about 11% (w/w) to about 18% (w/w). In other embodiments, the concentration of the glycol, glycol ether, glycol ester, or fatty acid ester is from about 12% (w/w) to about 17% (w/w) or from about 13% (w/w) to About 16% (w/w). In other embodiments of the invention, the concentration of the glycol, glycol ether or fatty acid ester is from about 12% (w/w) to about 14% (w/w) or from about 13% (w/w) to about 15% (w/w). In yet another embodiment, the glycol, glycol ether or fatty acid ester is present at a concentration of about 14% (w/w).

In all embodiments, other solvents and/or diluents may be used in the formulations of the invention. In one embodiment, long chain alkylamides may also be used, provided they provide the necessary solubility and physical and chemical stability to maintain the desired concentrations of fipronil and permethrin before and after application. These include systems employing cyclomethylene glyceryl ether, caprylamide and caprylamide such as N,N-dimethyldecylamide (DMDA). Cyclomethylene glyceryl ether is a (60:40) mixture of 5-hydroxy-1,3-dioxane and 4-hydroxymethyl-1,3-dioxolane. In one embodiment, the cyclomethylene glyceryl ether added to the formulation of the invention is a stabilized glyceryl glyceryl ether. Stabilized glyceryl ether typically contains 0.02% disodium EDTA, 0.02% N-propyl N-gallate, and 0.01% thiopropionic acid. However, in certain embodiments for topical application, the composition includes a neutral oil as a diluent.

additional active agent

In one embodiment, the present invention provides a topical composition comprising fipronil and permethrin in combination with one or more additional active agents. In certain embodiments, additional active agents combined with fipronil and permethrin may include, but are not limited to, acaricides, anthelmintics, insecticides, and other parasiticides of the various classes described herein.

In yet another embodiment, the topical composition may also include a veterinary therapeutic agent. Veterinary agents that may be included in the compositions of the present invention are well known in the art (see for example Plumb' Veterinary Drug Handbook, 5 ^th Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or The Merck Veterinary Manual, 9 ^th Edition, (January 2005)) and include but not limited to acarbose, acepromazine maleate, acetaminophen, acetazolamide, acetazolamide sodium, acetic acid, acetohydroxyamic acid, acetylcysteine, Acitretin, Acyclovir, Albendazole, Salbutamol Sulfate, Alfentanil, Allopurinol, Alprazolam, Allylgestrol, Amantadine, Amikacin Sulfate, Amantadine acid, amvaleramide hydrosulfate, aminophylline/theophylline, amiodarone, amitriptyline, amlodipine besylate, ammonium chloride, ammonium molybdate, amoxicillin, potassium clavulanate, amphoteric Mycin B deoxycholate, lipid-based amphotericin B, ampicillin, ampronium, antacid (oral), antivenom, apomorphine, apramycin sulfate, vitamin C, day Paraginase, aspirin, atenolol, atipamezole, atracurium besylate, atropine sulfate, aurnofin, aurothioglucose, azapirone, azathioprine, azithromycin, Baclofen, barbiturates, benazepril, betamethasone, bacholine, bisacodyl, subsalicylic acid, bleomycin sulfate, burgundone undecylenate, bromide compound, bromocriptine mesylate, budenoside, buprenorphine hydrochloride, buspirone hydrochloride, busulfan, butorphanol tartrate, cabergoline, salmon calcitonin, calcitriol, calcium salt, Captopril, carindencillin sodium, carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, cefotaxime Oxime Sodium, Cefotetan Disodium, Cefoxitin Sodium, Cefpodoxime Proxetil, Ceftazidime, Ceftiofur Sodium, Ceftiofur, Ceftriaxone Sodium, Cephalexin, Cephalosporin, Cefapirin, Charcoal (Activated Carbon) , chlorambucil, chloramphenicol, chlordiazepoxide , chlorine nitrogen +/- Clinium Bromide, Chlorthiazide, Chlorpheniramine Maleate, Chlorpromazine Hydrochloride, Chlorpropamide, Aureomycin, Chorionic Gonadotropin (HCG), Chromium, Cimetidine, Cyproterine Floxacin, cisapride, cisplatin, citrate, clarithromycin, clemastine fumarate, clenbuterol, clindamycin, clofazimine, clomipramine hydrochloride, clonazepam , clonidine, cloprostinol sodium, chlordiazepoxide Dipotassium, clorsulon, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), tecoctide, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, dacarbah oxazine, actinomycin D/actinomycin D, dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib, Lorelin acetate, desmopressin acetate, deoxycorticosterone pivalate, detomidine, dexamethasone, dexpanthenol, dexrazoxane, dextran, diazepam, diazepam diclofenac (oral), diclofenamide, diclofenac sodium, dicloxacillin, diethylcarbamate citrate, diethylstilbestrol (DES), difloxacin, digoxin, dihydrotachysterol (DHT), diltiazem , Dimenhydrinate, Dimercaprol/BAL, Dimethyl Sulfoxide, Dinoprost Tromethamine, Diphenylhydroxylamine, Disopyramide Phosphate, Dobutamine Hydrochloride, Docusate/ DSS, dolasetron mesylate, domperidone, dopamine hydrochloride, doramectin, doxapram hydrochloride, doxepin hydrochloride, doxorubicin hydrochloride, doxycycline, edetate calcium disodium, B Calcium diaminetetraacetate, ephenonium chloride, enalapril/enalaprilat, enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine, epoetin/erythropoietin, iprinox Cretin, Exetal, Erythromycin, Esmolol Hydrochloride, Estradiol Cypionate, Itacrylic Acid/Sodium Ethacrynate, Ethanol (Ethanol), Etidronate Sodium, Etodol Acid, etomidate, euthanasia w/ pentobarbital, famotidine, fatty acids (essential/omega), felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride, Fipronil, Florfenicol, Fluconazole, Flucytosine, Fludrocortisone Acetate, Flumazenil, Flumethasone, Flunixin Meglumine, Fluorouracil (5-FU), Fluoxetine Tin, fluticasone propylacetate, fluvoxamine maleate, fomepizole (4-MP), furazolidone, furosemide, gabapentin, gemcitabine HCL, gentamicin sulfate, glimepiride, glipizide Glucosamine, Glucagon, Glucocorticoid Agents, Glucosamine/Chondroitin Sulfate, Glutamine, Glibenclamide, Glycerin (Oral), Glycopyrronium Bromide, Gonadorelin, Griseofulvin, Guaiac Glyceryl ether, halothane, glutathione hemoglobin-200 ( ), heparin, hydroxyethyl starch, sodium hyaluronate, hydralazine, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, Midocardipropionate, Thiamycin-cilastatin Sodium, Imipramine, Amrinone Lactate, Insulin, Interferon alfa-2a (Human Recombinant), Iodide (Sodium/Potassium) , Ipeacac (Syrup), Sodium Ipodate, Iron Dextran, Isoflurane, Isoproterenol, Isotretinoin, Isoexulin, Itraconazole, Ivermectin, Kaolin/Pectin, Ketamine, ketoconazole, ketoprofen, ketorolac trometamol, lactulose, leuprolide, prosomthil, levetiracetam, levothyroxine sodium, lidocaine, lincomycin, Liothyronine sodium, lisinopril, lomustine (CCNU), lufenuron, lysine, magnesium, mannitol, marbofloxacin, nitrogen mustard, meclizine, meclofenamic acid , medetomidine, medium chain triglycerides, medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin, meloxicam, melphalan, medidine, mercaptopurine, Meropenem, Metformin, Methadone, Methazolamide, Urotropine Mandelate/Hippurate, Methimazole, Methionine, Methocarbamol, Methorbital Sodium, Methotrexate, Methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidaxole, mexiletine, mibordone, midazolam, mibimycin oxime, mineral Substance Oil, Minocycline, Misoprostol, Mitotane, Mitoxantrone, Morphine Sulfate, Moxidectin, Naloxone, Nandrolone Decanoate, Naproxen, Narcotics ( opium) agonist analgesics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin, sodium nitroprusside, nizatidine, novobiocin sodium , Nystatin, Octreotide Acetate, Osalazine Sodium, Omeprazole, Ondansetron, Opiate Antidiarrheals, Orbifloxacin, Oxacillin Sodium, Oxazepam, Oxybutynin Chloride, Oxymorphone, oxytetracycline, oxytocin, pamidronate disodium, pancreplipase, pancuronium bromide, paromomycin sulfate, parozetine, penicillamine, penicillins including penicillin, penicillin V potassium, pentazol Capryl, Pentobarbital Sodium, Xylpolysulfide Sodium, Pentoxifylline, Pergolide Mesylate, Phenobarbital, Phenoxybenzamine, Butazone, Phenylephrine, Phenylpropanolamine, Phenytoin, Pheromones, Parenteral Phosphoric Acids, Vitamin K1/Vitamin K-1, Pimobendan, Piperazine, Pilimycin, Piroxicam, Polysulfated Glycosaminoglycans, Ponazuril, Potassium chloride, prazosin, prednisolone/prednisone, primidone, procainamide, procarbazine, prochlorperazine, propantheline bromide, acne propionate Propionibacterium acnes injection, propofol, propranolol, protamine sulfate, pseudoephedrine, psyllium hydrogel, pyridostigmine bromide, mepyramine maleate, pyrimethamine, rice Palin, quinidine, ranitidine, rifampicin, s-adenosine methionine (SAMe), saline/hypertonic laxative, selamectin, selegiline/l-diprolene, sertraline, sevelamer, sevoflurane, silymarin / Milk thistle, sodium bicarbonate, sodium polystyrene sulfonate, sodium antimony gluconate, sodium sulfate, sodium thiosulfate, pituitary growth hormone, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase , streptozocin, dimercaptosuccinic acid, succinylcholine chloride, sucralfate, sufentanil citrate, sulfachlordazine sodium, sulfadiazine/trimethroprim, sulfamethoxazole/trimethoprim, Sulfadimentoxine (sulfadimentoxine), sulfadimentoxine/omeprene, sulfasalazine, taurine, tipoxalin, terbinafline, terbutaline sulfate, testosterone, tetracycline, thioarsamide sodium, vitamin B1, thioguanine, thiopental sodium, thiotepa, thyrotropin, tiamulin, ticarcillin disodium, tilmocsin/zolazepam, tilmocsin, tiopronin, tobramycin sulfate , Tocainide, Tolazoline, Tolfenamic Acid, Topiramate, Tramadol, Triamcinolone Acetonide, Trientine, Trilosteine, Alimazine Tartrate w/ Prednisolone, Tripyramine , tylosin, urdosiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium, verapamil, vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarin Sodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc acetate/zinc sulfate, zonisamide, and mixtures thereof.

In one embodiment of the invention, additional arylpyrazole compounds such as phenylpyrazoles may be included in the topical compositions of the invention. Arylpyrazoles are known in the art and are suitable for combination with isoxazoline compounds in the soft chewable compositions of the present invention. Examples of such arylpyrazole compounds include, but are not limited to, those described in U.S. Patent Nos. 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540;

In yet another embodiment of the present invention, one or more macrolides or lactams acting as acaricides, repellents and/or insecticides can be included in the composition of the present invention. For the avoidance of doubt, the term "macrolide" as used herein includes natural and synthetic or semi-synthetic avermectin and milbemycin compounds.

Macrolides that may be used in the compositions of the present invention include, but are not limited to, naturally occurring avermectins (including, for example, those designated _A1a , _A1b , _A2a , _A2b , _B1 a, components of B ₁ b, B ₂ a and B ₂ b) and milbemycin compounds, semi-synthetic avermectins and milbemycins, avermectin Avermectin monosaccharide compound and avermectin glycoside compound. Examples of macrolide compounds that can be used in the composition include, but are not limited to, abamectin, dematopidine, doramectin, emamectin, eprinomectin, ivermectin, Laidectin, lepimectin, selamectin, ML-1,694,554 and milbemycins, including but not limited to milbemectin, milbemycin D, milbemycin _Milbemycin A3, _Milbemycin A4, Milbemycin Oxime, Moxidectin and Nemadectin. Also included are the 5-oxo and 5-oxime derivatives of the avermectins and milbemycins.

Macrolide compounds are known in the art and can be readily obtained commercially or by synthetic techniques known in the art. See the extensive technical and commercial literature. For the avermectins, ivermectin and abamectin, see for example "Ivermectin and Abamectin", 1989, by MHFischer and H. Mrozik, William C. Campbell, published by Springer Verlag. or et al. (1981), "Avermectins Structure Determination", J. Am. Chem. Soc., 103, 4216-4221. For doramactin, see "Veterinary Parasitology", vol.49, No.1, July 1993, 5-15. For milbemycins, see inter alia Davies HG et al., 1986, "Avermectins and Milbemycins", Nat. Prod. Rep., 3, 87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336, US Patent No. 4,134,973 and EP 0 677 054, all of which are incorporated herein by reference.

The structures of avermectins and milbemycins are closely related, for example, both have a complex 16-membered macrolide ring. Natural product avermectins are disclosed in US Patent No. 4,310,519 and 22,23-dihydroabamectin compounds are disclosed in US Patent No. 4,199,569. Mention is also made in particular of US Patent Nos. 4,468,390, 5,824,653, EP 0 007 812 A1, UK Patent Specification 1 390 336, EP 0 002 916, and New Zealand Patent No. 237086. Natural mibimycins are described in US Patent No. 3,950,360 and in various references cited in "The Merck Index" 12 ^th ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996) . Latidine is described in "International Nonproprietary Names for Pharmaceutical Substances (INN)", WHO Drug Information, Vol. 17, No. 4, pp. 263-286, (2003).这些类别化合物的半合成衍生物是本领域熟知的并描述于例如US专利号5,077,308，4,859,657，4,963,582，4,855,317，4,871,719，4,874,749，4,427,663，4,310,519，4,199,569，5,055,596，4,973,711，4,978,677，4,920,148和EP 0 667 054 , which is incorporated herein by reference in its entirety.

In one embodiment, the topical composition of the present invention comprises an effective amount of avermectin, demametidine, doramectin, emamectin, eprinomectin, ivermectin, lamectin, Laidectin, lepimectin, selamectin, mibaycin, milbemycin D, milbemycin A ₃ , milbemycin A ₄ , At least one of mibimycin oxime, moxidectin or nemadectin, or a combination thereof. In yet another embodiment, the topical veterinary composition of the present invention may comprise an effective amount of abamectin, emamectin, eprinomectin, ivermectin, doramectin or selamectin at least one of them, or a combination thereof. In yet another embodiment, the topical compositions of the present invention may comprise an effective amount of at least one of ivermectin, mibemectin, milbemycin oxime, or moxidectin, or a combination thereof.

In yet another embodiment of the present invention, topical compositions comprising fipronil and permethrin may include a class of active agents known as insect growth regulators (IGRs). Compounds falling into this class are well known to practitioners and cover a wide range of different chemical classes. These compounds all work by interfering with the development or growth of insect pests. Insect growth regulators are described, for example, in U.S. Patent Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0179 022 or U.K. 2 140 010 and U.S. Patent Nos. 6,096,329 and 6,685,954 (all incorporated herein by reference).

In one embodiment of the composition of the invention, an IGR compound that mimics juvenile hormone or modulates juvenile hormone levels in insects may be included. Examples of juvenile hormone mimetics include azadirachtin, diphenoxyfen, fenoxycarb, methoprene, methoprene, methoprene, pyriproxyfen, tetrahydroazirachtin, and 4-chloro-2( 2-Chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy)pyridazin-3(2H)-one.

In yet another embodiment, the compositions of the invention include an IGR compound that is an inhibitor of chitin synthesis. Chitin synthesis inhibitors include imatabol, cyromazine, diflubenzuron, pyridoxuron, hexafluron, flubenzuron, hexaflumuron, lufenuron, tebufenozide, fluflubenzuron, triflubenzuron, 1 -(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea, 1-(2,6-difluoro-benzoyl)-3-(2 -Fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylurea and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethane base) phenylurea.

In certain embodiments, compositions of the present invention may include one or more anti-nematode agents including, but not limited to, active agents in the class of benzimidazoles, imidazothiazoles, ectoines, and organophosphate compounds. In certain embodiments, benzimidazoles may be included in the composition, including but not limited to, thiabendazole, thiabendazole, bubendazole, propoxyconazole, mebendazole, flubendazole, thiobenzene Azole, thiobenazole, carbendazim prothionate, cyclobendazole, fenthiocarbamate, thiophanate and its o,o-dimethyl analogs.

In other embodiments, the composition may include imidazothiazole compounds including, but not limited to, fenchong, baosunthia, and bumidazole.

In other embodiments, the compositions of the present invention may include ectoine active agents including, but not limited to, pyrantel, pyrimidine, and thienylhydropyrimidine.

Suitable organophosphate active agents include, but are not limited to, musphos, trichlorfon, dermafos, naphthalophos and dichlorvos, heptenylphos, memethaphos, monocrotophos, TEPP, and dimefenfos.

In other embodiments, the composition may include antinematode compounds, phenothiazines, piperazine as a neutral compound and various salt forms thereof, diethylcarbamate, phenols such as diiodonitrophenol, arsenic-containing agents such as sulfur Etyrosine, ethanolamines such as benzfenamide, thiaphenium chlorbenzenesulfonate, and methoxypyridine; cyanine dyes including promethionin chloride, promethionin pamoate, and iodothianin; Thiocyanates include p-isothiocyanate, suramin, hexynyl phthalate, and various natural products including, but not limited to, hygromycin B, alpha-anisemiinin, and kainic acid.

In other embodiments, the compositions of the present invention may include an anti-fluke agent. Suitable anti-fluke agents include, but are not limited to, milaxan such as melexin D and mirasan; praziquantel, clonazepam and its 3-methyl derivatives, oltipraz, methoxyanthrone, Lucanthone, hydroxyquine, thiocyanamide, nithiridazole, iodobenzonitrile, various bisphenol compounds known in the art including tobacol, thiochlorophene, thiochlorophene sulfoxide and Dinitrophen; various salicylanilide compounds including tribrosalanilide, hydroxyclosanilide, cloiodamide, rafoxanide, nitrobenzonitrile, bromothiosamide, and bromflunidide Salidamide and closantel; triclabendazole, acetaminophen, clorsulon, hytolin, and emetine.

Tapeworm repelling compounds that may also be advantageously used in the compositions of the present invention include, but are not limited to, arecoline in various salt forms, butadiamid, spiroxamate, nitrate, paromomycin, paromomycin, Longmycin II, Praziquantel and Exetel.

In other embodiments, the compositions of the present invention may include other active agents effective against arthropod parasites. Suitable active agents include, but are not limited to, bromikeline, chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromthion, ethyl bromthion, trithion, chlorpyramid, Chlorpyrifos, pentadophos, fenfos, diazinon, dimethophos, dimethoate, dioxafos, ethion, fenfen, fenitrothion, fenthion, fospirate, Iodophos, Malathion, Dibromophos, Phoxafos, Imidion, Phoxim, Aprofen, Pyrophos, Stirofos, Allethrin, Cyhalothrin, Cypermethrin, Deltamethrin, fenvalerate, flucyvalerate, permethrin, phenothrin, pyrethrins, resmethrin, benzyl benzoate, carbon disulfide, crotamiton, diflubenzuron, di Aniline, disulfiram, isobornyl thiocyanatoacetate, methoprene, sufelam, pirenonylbutoxide, rotenone, triphenyltin acetate, triphenyltin hydroxide, DEET, DEET, and Compounds 1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofurancarbaldehyde (MGK-11), 2-(2-ethylhexyl)-3a,4,7,7a- Tetrahydro-4,7-methano-1H-isoindole-1,3(2H)dione (MGK-264), Dipropyl-2,5-pyridinedicarboxylate (MGK-326) and 2-(octylthio)ethanol (MGK-874).

In yet another embodiment, antiparasitic agents that may be included in topical veterinary compositions may be biologically active peptides or proteins including, but not limited to, depsipeptides, which act by stimulating presynaptic receptors belonging to the secretin receptor family. The receptors act at the neuromuscular junction to cause paralysis and death of the parasite. In one embodiment of the depsipeptide, the depsipeptide is emodepside (see Willson et al., Parasitology, Jan. 2003, 126(Ptl):79-86).

In yet another embodiment, the topical compositions of the present invention may comprise an active agent of a neonicotinoid pesticide. Neonicotinoids bind to and inhibit insect-specific nicotinic acid acetylcholine receptors. In one embodiment, the neonicotinoid insecticide that can be included in the topical compositions of the present invention is imidacloprid. Such agents are described, for example, in U.S. Patent No. 4,742,060 or EP 0 892 060 (both of which are incorporated herein by reference). In yet another embodiment, the compositions of the present invention may comprise nitenpyram, a further active agent of neonicotinoid pesticides. The use of nitenpyram for controlling fleas is described in U.S. Patent No. 5,750,548, which is hereby incorporated by reference in its entirety.

In other certain embodiments of the present invention, the insecticide that can be combined with the composition of the present invention is a semicarbazone such as metaflumizone.

In yet another embodiment, the compositions of the present invention may advantageously include one or more other isoxazoline compounds known in the art. These active agents as being very effective against ectoparasites are described in US7,964,204 and WO2007/079162; ，US8,318,757，US2011/0144349，US8,053,452；US2010/0137612，US2010/0254959，US2011/152081，WO2012/089623，WO2012/089622，US8,119,671；US7,947,715；WO2102/120135，WO2012/107533，WO2011 /157748，US2011/0245274，US2011/0245239，US2012/0232026，US2012/0077765，US2012/0035122，US2011/0251247，WO2011/154433，WO2011/154434，US2012/0238517，US2011/0166193，WO2011/104088，WO2011/104087 ，WO2011/104089，US2012/015946，US2009/0143410，WO2007/123855A2，US2011/0118212，US7951828&US7662972，US2010/0137372A1，US2010/0179194A2，US2011/0086886A2，US2011/0059988A1，US2010/0179195A1，US7,897,630，U.S.7,951,828； WO2011/075591 and US2011/0152312, and US7,662,972, are hereby incorporated by reference in their entirety.

In yet another embodiment of the present invention, nodulisporic acid and its derivatives may be added to the compositions of the present invention. These compounds are used to treat or prevent infections in humans and animals and are described, for example, in U.S. Patent Nos. 5,399,582, 5,962,499, 6,221,894, and 6,399,786, which are hereby incorporated by reference in their entirety. The composition may include one or more of nodulisporic acid derivatives known in the art, including all stereoisomers, such as those described in the above-cited documents.

In yet another embodiment, insect repellent compounds such as aminoacetonitrile (AAD) compounds such as monepantel (ZOLVIX) and the like may be incorporated into the compositions of the present invention. These compounds are described eg in US7,084,280 by Ducray et al. (incorporated herein by reference); Sager et al., Veterinary Parasitology, 2009, 159, 49-54; Kaminsky et al., Nature vol.452, 13 March 2008, 176-181 .

Compositions of the present invention may also include arylopyrrol-2-ylcyanoethylamino compounds such as those described in Soll et al., US Patent No. 8,088,801 and US2010/0125089, incorporated herein by reference; Substituted amide derivatives are described in U.S. Patent No. 7,964,621 to Le Hir de Fallois, also incorporated herein by reference.

Compositions of the present invention may also include paraherquamide compounds and derivatives of these compounds, including derquantel (see Ostlind et al., Research in Veterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical and Veterinary Entomology, 1997, 11, 407-408). Paraquinillamides are a known class of compounds active against certain parasites that include a spirodioxepinoindole core (see Tett. Lett. 1981, 22, 135; J. Antibiotics 1990, 43, 1380, and J. Antibiotics 1991, 44, 492). Furthermore, structurally related marcfortines, such as marcfortines A-C, are also known and can be combined with the formulations according to the invention (see J.Chem.Soc.-Chem.Comm.1980, 601 and Tet.Lett.1981, 22, 1977). Additional descriptions of paraquinicillamide derivatives can be found in, for example, WO91/09961, WO92/22555, WO97/03988, WO01/076370, WO09/004432 and US2010/0197624, US Patent 5,703,078 and US Patent 5,750,695, which are incorporated by reference All incorporated herein.

In yet another embodiment of the invention, the composition may include a spinosyn active agent produced by the soil actinomycete Saccharopolyspora spinosa (see, e.g., Salgado V.L. and Sparks T.C., " The Spinosyns: Chemistry, Biochemistry, Mode of Action, and Resistance, "Comprehensive Molecular Insect Science, vol.6, pp.137-173, 2005) or semi-synthetic spinosoid-like active agents. Spinosyns are generally referred to as factors or components A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, or Y, and any one or combination of these components can be used in the composition of the present invention. Spinosyn compounds may be 5,6,5-tricyclic ring systems fused to 12-membered macrolides, neutral sugars (rhamnose), and amino sugars (forosamine). These and other natural spinosyn compounds, including the Saccharopolyspora pagona-produced 21-butenyl spinosyn that may be used in the compositions of the present invention, may be produced by fermentation via conventional techniques known in the art. Other spinosyn compounds that may be used in the compositions of the present invention are disclosed in U.S. Patent Nos. 5,496,931; 5,670,364; 5,591,606; 5,571,901; 5,202,242; Spinosad compounds may include, but are not limited to, spinosyn A, spinosyn D, spinosyn, spinosyn, or combinations thereof. Spinosyn is a combination of spinosyn A and spinosyn D, while ethyl spinosyn is 3'-ethoxy-5,6-dihydrospinosyn J and 3'-ethoxy Combination of Quilocidin L.

Typically, additional active agents are included in dosage units of the invention in amounts of from about 0.1 μg to about 1000 mg. Generally, the active agent may be included in an amount of about 10 μg to about 500 mg, about 10 μg to about 400 mg, about 1 mg to about 300 mg, about 10 mg to about 200 mg, or about 10 mg to about 100 mg. More typically, the active agent will be present in the compositions of the invention in an amount from about 5 mg to about 50 mg.

Depending on the potency of the active agent, the concentration of additional active agent in the topical compositions of the present invention will generally be from about 0.01% to about 30% (w/w). In certain embodiments for very potent active agents including, but not limited to, macrolide active agents, the concentration of the active agent is generally about 0.01% to about 10% (w/w), about 0.01 to about 1% (w/w), about 0.01% to about 0.5% (w/w), about 0.1% to about 0.5% (w/w), or about 0.01% to about 0.1% (w/w). In other embodiments, the concentration of active agent is generally from about 0.1% to about 2% (w/w) or from about 0.1% to about 1% (w/w).

In other embodiments, additional active agents are generally present at higher concentrations to achieve the desired potency. In certain embodiments, the active agent is present at a concentration of about 1% to about 30% (w/w), about 1% to about 20% (w/w), or about 1% to about 15% (w/w) exist. In other embodiments, the active agent is present in the composition at a concentration of about 5% to about 20% (w/w), or about 5% to about 15% (w/w).

In various embodiments of the invention, additional active agents may be included in the composition to deliver a dose of from about 0.001 mg/kg to about 50 mg/kg or from about 0.5 mg/kg to about 50 mg/kg of the animal's body weight. In other embodiments, the active agent is generally present in an amount sufficient to deliver a dose of about 0.05 mg/kg to about 30 mg/kg, about 0.1 mg/kg to about 20 mg/kg. In other embodiments, the active agent is in an amount sufficient to deliver a dose of about 0.1 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 1 mg/kg, or about 0.5 mg/kg to about 50 mg/kg per animal body weight exist.

In certain embodiments of the present invention, wherein the additional active agent is a highly potent compound such as a macrolide or other effective compound, the active agent provides from about 0.001 mg/kg to about 5 mg/kg, about 0.001 mg/kg It is present at a dose concentration of up to about 0.1 mg/kg, or about 0.001 mg/kg to about 0.01 mg/kg. In other embodiments, the active agent is present in an amount sufficient to deliver a dose of about 0.01 mg/kg to about 2 mg/kg, or about 0.1 mg/kg to about 1 mg/kg per animal body weight. In other embodiments, the additional active agent may be present in an amount to deliver a dose of from about 1 μg/kg to about 200 μg/kg, or from about 0.1 mg/kg to about 1 mg/kg of the animal's body weight.

method and use

In one embodiment, the subject matter of the present application relates to methods of treating and/or controlling parasitic infestation in animals. The method includes administering to the animal an effective amount of a formulation described herein. Surprisingly, it has been found and disclosed herein that at specific concentrations, fipronil and permethrin have surprisingly enhanced repellent activity against stable flies. In one embodiment it was surprisingly found that formulations according to the invention with the combination of fipronil and permethrin have significantly higher repellency against stable flies compared to formulations containing permethrin alone For avoidance effect, the individual permethrins were administered at the same concentration to deliver the same dose. The observed enhanced repellent efficacy was unexpected because while fipronil is a very effective insecticide, it is not known to have repellent efficacy against ectoparasites. Accordingly, one method of the invention relates to combating pest infestation by parasitic flies, including stable flies (Stomoxys calcitrans) and horn flies (Haematobia irritans), among other fly species.

In other embodiments, the uses and methods of the present invention are for the treatment and/or prevention of parasitic infestation and/or infection by pests, including those of the order Anoplura such as Haematopinus spp. ), Linognathus spp., Solenopotes spp., Pediculus spp., Pthirus spp.; Mallophaga such as Trimenopon spp.), Menopon spp., Eomenacanthus spp., Menacanthus spp., Trichodectesspp., Felicola spp., Damalinea spp., Cattle Feather Lice (Bovicola spp.); Diptera (Diptera), Brachycera (Brachycera), for example Chrysops spp., Tabanus spp., Musca spp., tooth Hydrotaea spp., Muscina spp., Haematobosca spp., Haematobia spp., Stomoxys spp., Stomoxys spp. ( Fannia spp.), Glossina spp., Lucilia spp., Calliphoraspp., Auchmeromyia spp., Cordylobia spp., Cone Cochliomyias pp., Chrysomyia spp., Sarcophaga spp., Wohlfahrtias pp., Gasterophilus spp., Oedemagena spp. , Hypodermaspp., Oestrus spp., Rhinoestrus spp., Melophagusspp., Hippobosca spp.; Diptera ), Nematocera such as Culex spp., Aedes spp., Anopheles spp., Culicoidesspp., Phlebotom us spp.), Simulium spp.; Siphonaptera such as Ctenocephalides spp., Echidnophaga spp., Ceratophyllus spp., Ceratophyllus spp. (Pulex spp.); Metastigmata such as Hyalomma spp., Rhipicephalus spp., Boophilus spp., Amblyomma spp. ), Haemaphysalis spp., Dermacentor spp., Ixodes spp., Argas spp., Otobius spp.; Medium Mesostigmata, such as Dermanyssus spp., Ornithonyssus spp., Pneumonyssus spp.; former Prostigmata, such as Acarina ( Cheyletiella spp.), Psorergates pp., Myobia spp., Demodex spp., Neotrombiculas pp.; Acarus spp., Myocoptes spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp. .), Notoedres spp., Knemidocoptes spp., Neoknemidocoptes spp., Cytodites spp., Laminosioptes spp.; and Fleas (from the order Siphonaptera such as Ctenocephalides spp., Echidnophaga spp., Ceratophyllus spp., Pulex spp.), ticks (Glass Hyalomma spp., Rhipicephalus spp., Boophilus spp., Ambly omma spp.), Haemaphysalis spp., Dermacentor spp., Ixodes spp., Argas spp., Ornithodorus spp. ), Otobius spp.) and especially the above-mentioned Diptera (Chrysops spp., Tabanus spp., Musca spp. .), Hydrotaea spp., Muscinaspp., Haematobosca spp., Haematobia spp., Stomoxysspp., Toilet flies Fannia spp., Glossina spp., Lucilia spp., Calliphora spp., Auchmeromyia spp., Cordylobia spp. ), Cochliomyia spp., Chrysomyia spp., Sarcophaga spp., Gasterophilus spp., Oedemagena spp., Derma (Hypoderma spp., Oestrus spp., Rhinoestrus spp., Melophagus spp., Hippobosca spp.).

In yet another embodiment, the subject matter disclosed herein relates to a method of cleaning the fur and skin of an animal by removing the parasites present and their waste and excreta and administering to the animal a formulation as described herein. Thus, the treated animals exhibit a more visually pleasing and tactilely more pleasing coat.

The term "animal" as used herein refers to any mammal or bird. In particular cattle, sheep, horses, pigs, chickens and dogs would benefit from administration of the compositions disclosed herein because they can become infested with parasites which are effectively controlled by the compositions. Useful and breeding animals include mammals such as cattle, horses, zebras, sheep, pigs, goats, camels, yaks, buffaloes, donkeys, fawns, reindeer, rodents, fur animals such as mink, chinchilla, raccoon, Birds such as chickens, chicks, geese, turkeys, quail and ducks. Domesticated animals include dogs, and special emphasis is placed on the handling of dogs.

Various methods of formulating parasiticidal formulations are known in the art. These include oral formulations, dietary supplements, powders, dermal solutions (pour-ons or smears), sprays, drenches, baths, showers, sprays, powders, ointments, shampoos and creams.

Of particular interest are formulations for topical application of parasiticidal active agents, known in the art as smear or pour-on formulations. Each type of formulation has different properties. For example, pour-on solutions containing 1-N-phenylpyrazole derivatives such as fipronil are known in the art and described in, for example, U.S. Patent No. 6,010,710, U.S. Patent No. 6,413,542, U.S. Patent No. 6,001,384 and U.S. Patent No. 6,413,542. Lotion formulations are a well-known technique for topical delivery of certain antiparasitic agents with desired physicochemical properties to localized areas of the host. For example, U.S. Patent No. 5,045,536 describes such formulations for ectoparasites. Other paint formulations include U.S. Patent No. 6,426,333 and U.S. Patent No. 6,482,425. All of these references are incorporated herein in their entirety.

In one embodiment, the composition is a paint formulation comprising about 2% (w/w) to about 10% (w/w) fipronil; about 30% (w/w) to about 55% ( w/w) permethrin; and glycol, glycol ether, glycol ester, fatty acid ester or neutral oil and N-methylpyrrolidone, wherein said glycol, glycol ether, glycol ester, fatty acid Glycols, glycol ethers, glycol esters, fatty acid esters, or neutral oils of esters or neutral oils and N-methylpyrrolidone at about 1:1.8 to about 1:2.8 or about 1:2.0 to about 1:3.5 :NMP ratio exists, and further wherein said composition is a liquid having a volume of about 0.5 mL to about 10 mL. In yet another embodiment, the volume of the varnish composition is from about 1 mL to about 6 mL.

In yet another embodiment, the composition is a paint formulation comprising at least about 5% (w/w) fipronil; at least about 40% (w/w) permethrin; and glycols, glycol ethers, Glycol ester, fatty acid ester or neutral oil and N-methylpyrrolidone, wherein said glycol, glycol ether, glycol ester, fatty acid ester or neutral oil and N-methylpyrrolidone are in a ratio of about 1:1.8 Glycol, glycol ether, glycol ester, fatty acid ester or neutral oil:NMP weight:weight ratio of to about 1:2.8 or about 1:2.0 to about 1:3.5 exists, and further wherein said combination The substance is a liquid having a volume of about 0.5 mL to about 10 mL. In yet another embodiment, the volume of the varnish composition is from about 1 mL to about 6 mL.

In one embodiment, the composition is a paint formulation comprising at least about 5% (w/w) fipronil; at least about 40% (w/w) permethrin; and glycols, glycol ethers, Glycol ester, fatty acid ester or neutral oil and N-methylpyrrolidone, wherein said glycol, glycol ether, glycol ester, fatty acid ester or neutral oil and N-methylpyrrolidone are in a ratio of about 1:2.5 Glycols, glycol ethers, glycol esters, fatty acid esters, or neutral oils:NMP to a weight:weight ratio of about 1:3.5 or about 1:25 to about 1:3.0 is present, and further wherein the combination The substance is a liquid having a volume of about 0.5 mL to about 10 mL. In yet another embodiment, the volume of the varnish composition is from about 1 mL to about 6 mL.

In yet another embodiment, the composition is a paint formulation comprising about 5% (w/w) to about 15% (w/w) fipronil; about 40% (w/w) to about 55% ( w/w) permethrin; and glycol, glycol ether, glycol ester, fatty acid ester or neutral oil and N-methylpyrrolidone, wherein said glycol, glycol ether, glycol ester, fatty acid Glycols, glycol ethers, glycol esters, fatty acid esters, or neutral oils of esters or neutral oils and N-methylpyrrolidone at about 1:1.8 to about 1:2.8 or about 1:2.0 to about 1:3.5 :NMP present in a weight:weight ratio, and further wherein the composition is a liquid having a volume of about 0.5 mL to about 10 mL. In yet another embodiment, the volume of the varnish composition is from about 1 mL to about 6 mL.

In yet another embodiment, the composition is a paint formulation comprising about 5% (w/w) to about 15% (w/w) fipronil; about 40% (w/w) to about 55% ( w/w) permethrin; and glycol, glycol ether, glycol ester, fatty acid ester or neutral oil and N-methylpyrrolidone, wherein said glycol, glycol ether, glycol ester, fatty acid Ester or neutral oil and N-methylpyrrolidone in about 1:2.5 to about 1:3.0 or about 1:2.5 to about 1:3.5 glycol, glycol ether, glycol ester, fatty acid ester or neutral oil :NMP present in a weight:weight ratio, and further wherein the composition is a liquid having a volume of about 0.5 mL to about 10 mL. In yet another embodiment, the volume of the varnish composition is from about 1 mL to about 6 mL.

In yet another embodiment, the composition is a paint formulation comprising about 5% (w/w) to about 10% (w/w) fipronil; about 40% (w/w) to about 50% ( w/w) permethrin; and glycol, glycol ether, glycol ester, fatty acid ester or neutral oil and N-methylpyrrolidone, wherein said glycol, glycol ether, glycol ester, fatty acid Glycols, glycol ethers, glycol esters, fatty acid esters, or neutral oils of esters or neutral oils and N-methylpyrrolidone at about 1:1.8 to about 1:2.8 or about 1:2.0 to about 1:3.5 :NMP present in a weight:weight ratio, and further wherein the composition is a liquid having a volume of about 0.5 mL to about 10 mL. In yet another embodiment, the volume of the varnish composition is from about 1 mL to about 6 mL.

In yet another embodiment, the composition is a paint formulation comprising about 5% (w/w) to about 10% (w/w) fipronil; about 40% (w/w) to about 50% ( w/w) permethrin; and glycol, glycol ether, glycol ester, fatty acid ester or neutral oil and N-methylpyrrolidone, wherein said glycol, glycol ether, glycol ester, fatty acid Ester or neutral oil and N-methylpyrrolidone in about 1:2.5 to about 1:3.5 or about 1:2.5 to about 1:3.0 glycol, glycol ether, glycol ester, fatty acid ester or neutral oil :NMP present in a weight:weight ratio, and further wherein the composition is a liquid having a volume of about 0.5 mL to about 10 mL. In yet another embodiment, the volume of the varnish composition is from about 1 mL to about 6 mL.

The topical compositions of the present invention can be administered in several ways. Administration includes contacting the fur and/or skin of the animal with the composition. In one embodiment, the formulation is a paint or pour-on formulation. These formulations were applied to the animal's back, at one or two points along the topline for pour-on formulations and on the back for paint products. In one embodiment, the formulation is administered to the animal in a highly localized area of the animal, preferably between the shoulder blades. In yet another embodiment, the localized region has a surface area of less than 10 cm ² , in particular an area of 5 to 10 cm ² . The contacting or administering can be done prophylactically as well as therapeutically.

Administration of the formulation can be intermittent and can be given daily, weekly, biweekly, monthly, bimonthly, quarterly, or even for a longer duration. The time interval between treatments depends on various factors such as the target parasite, the degree of infestation, the type of mammal or bird being treated and its habitat. The skill of the practitioner is sufficient to determine the particular period of administration for a particular situation. The presently described approach involves continuous combating of parasites in environments where animals are subjected to intense parasitic stress, where dosing is much less frequent than daily dosing in this case. For example, in one embodiment, treatment according to the invention is performed monthly on a mammal, such as a dog.

In certain embodiments, the liquid formulations according to the invention are suitable for spray application, wherein spray application can be carried out, for example, with a pump spray or an aerosol spray (pressurized spray). For certain indications, the formulations can also be used as dips after dilution with water; in this case, the formulations should contain emulsifying additives. In one embodiment, the composition is applied as a pour-on and paint formulation. Paint application is particularly preferred. The formulations according to the invention are distinguished by their excellent compatibility with conventional "single-dose" plastic straws and their storage stability in various climatic zones. They have low viscosity and can be applied easily.

Liquid formulations according to the invention can be prepared by mixing appropriate amounts of the components with one another, for example using conventional stirred tanks or other suitable equipment. It is also possible to operate under a protective atmosphere or to remove oxygen by other means if the composition so requires. Rub on formulations can be prepared by dissolving the active ingredient in a pharmaceutically or veterinarily acceptable vehicle. Alternatively, rub-on formulations can be prepared by encapsulating the active ingredient so as to leave residues of the therapeutic agent on the surface of the animal. Depending on the species of host animal to be treated, the severity and type of infection and the body weight of the host, these formulations will vary with the weight of therapeutic agents in combination.

In certain embodiments, the compositions described herein are free of visible solids and are clear, but not necessarily water-clear solutions having the described synergistic amounts of fipronil completely dissolved therein. and permethrin. Despite the high concentration of actives present in the composition, the two-component solvent system ensures the following goals: no crystallization on the pelt and the maintenance of the hide's cosmetic appearance without the tendency to stick or sticky appearance.

In certain embodiments, the formulations disclosed herein can also include synergists. Synergists are understood in this application to mean compounds which do not have the desired activity on their own, but which, as mixing partners, increase the activity of the active compounds. Butyrate, MGK264, verbutin, S,S,S-tributylphosphorotrithioate can be mentioned by way of example.

Although not required, the composition can also include a stability enhancer. A "stability enhancer" is a compound that enhances the stability of an active agent compared to the stability of the active agent in the absence of the stability enhancer. Examples of stability enhancers include glycerol ether and polyethylene glycol (eg, PEG200). Other stability enhancers are well known in the art. In a specific embodiment, small amounts of glyceryl glyceryl ether, such as 5% or less, can be added. In certain embodiments, it may be desirable to add PEG200 to the formulations of the present invention to support the stability enhancing and solvency functions of glyceryl glyceryl ether.

The invention also provides titration of the amount of stability enhancer added to the formulation of the invention. For example, in embodiments where the stability enhancer is glyceryl ether, the amount of glyceryl ether can be titrated such that optimal stability of the fipronil and permethrin combination is achieved in the formulation. accomplish. Stability enhancers may be present in formulations of the invention in lower amounts such as about 5% w/v or less (eg 1.5% w/v). In other embodiments, the stability enhancer is present in an amount of about 5-25% w/v, such as 15% w/v.

In certain embodiments, the oily solutions according to the invention may comprise, in addition to the glycol ether, a diluent or vehicle and a solvent (organic solvent) for one or more active agents. However, due to the ability of the two-component solvent system described herein to solvate permethrin and fipronil, the use of added solubility enhancers is desirably reduced.

Additionally, although not required, if desired, a crystallization inhibitor can be used in the composition. These include: polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerin, sorbitol, or polyoxyethyleneated sorbitan Esters of sugar alcohols; lecithin or sodium carboxymethylcellulose; or acrylic acid derivatives such as methacrylic acid, etc., anionic surfactants such as alkaline stearates, especially sodium, potassium or ammonium stearate; Calcium stearate or triethanolamine stearate; sodium rosinate; alkyl sulfates, especially sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctylsulfosuccinate or fatty acids, especially those derived from coconut oil, cationic surfactants such as water ^- soluble quaternary ammonium salts of the formula N ⁺ R'R"R"'R""Y-, wherein R', R", R The "' and R"" residues are the same or different optionally hydroxylated hydrocarbon residues and Y ^- is an anion of a strong acid such as halide, sulfate and sulfonate anion; cetyltrimethylammonium bromide is One of the cationic surfactants that can be used, the formula N ⁺ HR'R"R"'Y ^- amine salt, wherein the R', R" and R"' residues are the same or different optionally hydroxylated hydrocarbon residues And Y ^- as defined above; octadecylamine hydrochloride is one of the cationic surfactants that can be used, nonionic surfactants such as esters of sorbitan optionally polyoxyethylenated, especially Polysorbate 80, or Polyoxyethylenated Alkyl Ether; Polyethylene Glycol Stearate, Polyoxyethylenated Castor Oil Derivative, Polyglyceryl Esters, Polyoxyethylene fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and propylene oxide, amphoteric surfactants such as substituted betaines lauryl compounds, or at least two of the compounds listed above mixture of species.

Ability to use crystallization inhibitor pairings. The aforementioned pairing includes, for example, a combination of a polymer-type film-forming agent and a surfactant. These agents are chosen especially from the compounds mentioned above as crystallization inhibitors. In certain embodiments of the present invention, polymeric film formers include various grades of polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and copolymers of vinyl acetate and vinylpyrrolidone. In one embodiment, the surfactants include those consisting of nonionic surfactants, including esters of polyoxyethylenated sorbitan and polyoxyethylenated castor oil derivatives, and In particular the various grades of polysorbate such as polysorbate 80.

Film formers and surfactants can be incorporated in similar or identical amounts, especially within the total limits of crystallization inhibitors mentioned elsewhere.

Alternative or additional organic solvents that can be used in the present invention include acetyl tributyl citrate, fatty acid esters such as fatty acid dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diethylene glycol, dimethylacetamide, dimethylformamide, dimethyl sulfoxide (DMSO), diethyl sebacate, isosorbide dimethyl ether, dipropylene glycol n-butyl ether, ethanol, Isopropanol, Methanol, Ethylene Glycol Monoethyl Ether, Ethylene Glycol Monomethyl Ether, Monomethylacetamide, Dipropylene Glycol Monomethyl Ether, Liquid Polyoxyethylene Glycol, Propylene Glycol, 2-Pyrrolidone, Ethylene glycol; glycol esters including ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl ether acetate, ethylene glycol monomethyl ether acetate, etc.; and diethyl phthalate esters, or mixtures of at least two of these solvents.

Furthermore, mention may be made in particular of other possible ingredients such as vegetable oils: soybean oil, peanut oil, castor oil, corn oil, cotton oil, olive oil, grapeseed oil, sunflower oil, etc.; mineral oils such as petrolatum, paraffin, silicone, etc.; aliphatic Or cyclic hydrocarbons or alternatively eg medium chain (especially C8 to C12) triglycerides.

Softeners and/or spreading agents and/or film formers may additionally be added, which agents are chosen especially from: polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol , mannitol, glycerin, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose, silicone oils, polydiorganosiloxane oils, especially polydimethyl Silicone (PDMS) oils such as those containing silanol functionality, or 45V2 oil, anionic surfactants such as alkaline stearates especially sodium, potassium or ammonium stearate; stearic acid Calcium, triethanolamine stearate; sodium abietate; alkyl sulfates, especially sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate; fatty acids, Especially those derived from coconut oil, cationic surfactants such as water ^- soluble quaternary ammonium salts of the formula N ⁺ R'R″R″'R″″, Y-, wherein the residues R′, R″, R″ ' and R"" are optionally hydroxylated hydrocarbon residues and Y ^- is an anion of a strong acid such as halide, sulfate and sulfonate anion; among the cationic surfactants that can be used especially cetyltrimethyl Ammonium bromide, formula N ⁺ HR"R"'R"", Y ^- amine salt, wherein the residues R", R"' and R"" are optionally hydroxylated hydrocarbon residues and Y ^- as defined above ; among the cationic surfactants that can be used are especially stearylamine hydrochloride, nonionic surfactants such as sorbitan esters, which are optionally polyoxyethylenated, especially polysorbates 80. Polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrene ethers; polyethylene glycol stearate, polyoxyethylenelated castor Sesame oil derivatives, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide, amphoteric surfactants such as substituted betaines a lauryl compound of a salt; or a mixture of at least two of these agents. Softeners can be used in proportions of 0.1 to 10%, especially 0.25 to 5%, by volume.

In certain embodiments, the liquid carrier contains an organic solvent and optionally an organic co-solvent. In one embodiment, the organic solvent used in the liquid carrier vehicle has a dielectric constant of about 10 to about 35. In yet another embodiment, the organic solvent has a dielectric constant of about 20 to about 30, and the amount of the solvent in the total composition represents the remaining amount to achieve 100% of the composition. A person skilled in the art can readily select a suitable solvent based on these parameters.

In certain embodiments, the organic co-solvent used in the liquid carrier vehicle has a boiling point of less than about 100°C. In yet another embodiment, the organic co-solvent has a boiling point of less than about 80°C, and has a dielectric constant of from about 10 to about 40. In yet another embodiment, the organic co-solvent has a dielectric constant of about 20 to about 30. The co-solvent can advantageously be present in the composition at a weight/weight (w/w) ratio relative to the solvent of about 1/15 to about 1/2. In one embodiment, the co-solvent is volatile so as to act inter alia as a drying accelerator, and can be mixed with water and/or with a solvent. Again, suitable solvents are readily selected by those skilled in the art based on these parameters.

Organic solvents for liquid carriers include generally acceptable organic solvents known in the art of formulation. These solvents can be found, for example, in Remington Pharmaceutical Science, 16th Edition (1986). These solvents include, for example, acetone, ethyl acetate, methanol, ethanol, isopropanol, dimethylformamide or dichloromethane. Those solvents suitable for topical application are preferred.

In yet another embodiment, the subject matter disclosed herein is directed to a solvent system comprising A) NMP and B) a glycol, glycol ether, glycol ester, fatty acid ester, or neutral oil, wherein N-methylpyrrolidone and glycol , glycol ether, glycol ester, fatty acid ester or neutral oil by weight of glycol, glycol ether, glycol ester, fatty acid ester or neutral oil from about 1:1.8 to about 1:2.8:NMP: A weight ratio exists wherein dissolved in the solvent system are two active agents selected from an N-arylpyrazole and a pyrethroid. In one such embodiment, the subject of the present application relates to formulations comprising a pyrethroid at a concentration of about 30% w/w to about 55% w/w; at a concentration of about 2% w/w to about 10% w A kind of N-aryl pyrazole of /w; And A) glycol, glycol ether, glycol ester, fatty acid ester or neutral oil and B) NMP, wherein glycol, glycol ether, glycol ester, The fatty acid ester or neutral oil and NMP are present in a weight:weight ratio of about 1:1.8 to about 1:2.8, glycol, glycol ether, glycol ester, fatty acid ester or neutral oil:NMP.

In yet another embodiment, the formulation comprises a pyrethroid at a concentration of at least about 40% w/w; an N-arylpyrazole at a concentration of at least about 5% w/w; and A) a diol, di Alcohol ether, glycol ester, fatty acid ester or neutral oil and B) NMP, wherein glycol, glycol ether, glycol ester, fatty acid ester or neutral oil and NMP are in the ratio of about 1:1.8 to about 1:2.8 Or a weight:weight ratio of glycol, glycol ether, glycol ester, fatty acid ester, or neutral oil:NMP of about 1:2.0 to about 1:3.5 is present.

In yet another embodiment, the formulation comprises a pyrethroid at a concentration of at least about 40% w/w; an N-arylpyrazole at a concentration of at least about 5% w/w; and A) a diol, di Alcohol ether, glycol ester, fatty acid ester or neutral oil and B) NMP, wherein glycol, glycol ether, glycol ester, fatty acid ester or neutral oil and NMP are in the ratio of about 1:2.0 to about 1:3.0 , Glycol, glycol ether, glycol ester, fatty acid ester or neutral oil: NMP weight: weight ratio exists.

In yet another embodiment, the formulation comprises a pyrethroid at a concentration of at least about 40% w/w; an N-arylpyrazole at a concentration of at least about 5% w/w; and A) a diol, di Alcohol ether, glycol ester, fatty acid ester or neutral oil and B) NMP, wherein glycol, glycol ether, glycol ester, fatty acid ester or neutral oil and NMP are in the ratio of about 1:2.5 to about 1:3.5 The weight:weight ratio of glycol, glycol ether, glycol ester, fatty acid ester or neutral oil:NMP present.

In yet another embodiment, the formulation comprises a pyrethroid at a concentration of at least about 40% w/w; an N-arylpyrazole at a concentration of at least about 5% w/w; and A) a diol, di Alcohol ether, glycol ester, fatty acid ester or neutral oil and B) NMP, wherein glycol, glycol ether, glycol ester, fatty acid ester or neutral oil and NMP are in the ratio of about 1:2.5 to about 1:3.0 The glycol, glycol ether, glycol ester, fatty acid ester or neutral oil:NMP ratio present.

In a particular aspect of this embodiment, the subject of the present application relates to a pesticide composition comprising: about 2% (w/w) to about 15% (w/w) N-arylpyrazole; about 30% (w/w ) to about 55% (w/w) pyrethroids; A) glycols, glycol ethers, glycol esters, fatty acid esters, or neutral oils, and B) NMP, wherein the glycols, glycol ethers, Glycol esters, fatty acid esters or neutral oils and NMP at about 1:1.8 to about 1:2.8 or about 1:2.0 to about 1:3.5, about 1:2.0 to about 1:3.0, about 1:2.5 to about Glycol, glycol ether, glycol ester, fatty acid ester, or neutral oil:NMP weight:weight ratio of 1:3.5 or about 1:2.5 to about 1:3.0 is present; and optionally an antioxidant.

Useful concentrations of N-arylpyrazoles in the compositions are from about 2% (w/w) to about 15% (w/w). In yet another embodiment, the concentration of N-arylpyrazole is from about 3% (w/w) to about 10% (w/w) or from about 4% (w/w) to about 8% (w/w ). In yet another embodiment, the concentration of N-arylpyrazole is about 6% (w/w).

Useful concentrations of pyrethroids in the compositions of the present invention are from about 35% (w/w) to about 50% (w/w). In yet another embodiment, the pyrethroid is present at a concentration of about 40% (w/w) to about 48% (w/w). In yet another embodiment, the concentration of pyrethroids is from about 42% (w/w) to about 47% (w/w). In yet another embodiment, the concentration of pyrethroids in the composition is about 45% (w/w).

N-芳基吡唑和它们的杀寄生物和杀螨活性已知自US20060014802A1，W02005090313A1，FR2834288A1，W09828277，US6069157，WO0031043，DE19824487，WO9804530，WO9962903，EP0933363，EP0911329，WO9856767，US5814652，WO9845274，WO9840359，WO9828279 ，WO9828278，DE19650197，WO9824767，EP0846686，EP0839809，WO9728126，EP0780378，GB2308365，US5629335，WO9639389，US5556873，EP0659745，US5321040，EP0511845，和EP0234119，EP0295117，和WO98/24769。 These references are incorporated herein in their entirety.

Similarly, pyrethroids have a relatively broad parasiticidal action, and some representatives can also show a good acaricidal effect. As discussed above, the different physicochemical properties of the substances used require special formulations. However, the solvent systems described herein have been shown to solvate high concentrations of permethrin and fipronil in combination with it.

In certain embodiments, compositions comprising combinations of N-arylpyrazoles and pyrethroids may contain cyanopyrethroids (e.g. bifenthrin), type-1 pyrethroids (e.g. permethrin ) or one or more of non-ester pyrethroid (etoproxil) types. In other embodiments, the composition may include the pyrethroid α-cyanopyrethroid (e.g., α-cypermethrin, cyfluthrin, lambda-cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate , flucyvalerate, bifenthrin, fluvalinate); type-1 pyrethroids (eg, allethrin, bioallethrin, permethrin, phenethrin, benzfur one or more of non-ester pyrethroids (e.g., etofenprox, benzafen, flusalthrin).

In addition, it is also possible to use the active compounds in the form of their solvates, especially hydrates. Solvates are to be understood as meaning solvates, especially hydrates, of the active compounds themselves and solvates, especially hydrates, of their salts.

Where applicable, pharmaceutically or veterinarily acceptable acid or base salts of the active compounds provided herein are also contemplated. The term "acid" contemplates all pharmaceutically or veterinarily acceptable inorganic or organic acids. Inorganic acids include inorganic acids such as hydrohalic acids such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Organic acids include all pharmaceutically or veterinarily acceptable aliphatic, cycloaliphatic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. Preferred acids are straight-chain or branched, saturated or unsaturated C1-C20 aliphatic carboxylic acids, optionally substituted by halogen or hydroxyl groups, or C6-C12 aromatic carboxylic acids. Examples of such acids are acetic acid, carbonic acid, formic acid, fumaric acid, acetic acid, propionic acid, isopropionic acid, valeric acid, alpha-hydroxy acids such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methanesulfonic acid, and salicylic acid. Examples of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tartaric acid and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids include all pharmaceutically or veterinarily acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and phenylstearic acid. Other acids include gluconic acid, glucoheptonic acid, lactobionic acid, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic acid, pamoic acid, glutamic acid or aspartic acid.

The term "base" contemplates all pharmaceutically or veterinarily acceptable inorganic or organic bases. Such bases include, for example, alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium or calcium salts. Organic bases include typical hydrocarbyl and heterocyclic amine salts including, for example, morpholine and piperidine salts.

In one embodiment, the liquid carrier may also comprise a microemulsion. Microemulsions are also well suited for use as liquid carrier vehicles. Microemulsions are generally quaternary systems comprising an aqueous phase, an oil phase, surfactants, and cosurfactants. They can be translucent and isotropic liquids.

Microemulsions consist of a stable dispersion of droplets of an aqueous phase in an oily phase, or conversely of an oily phase in an aqueous phase. The size of these droplets is less than 200 nm (versus 1000 to 100000 nm for emulsions). The interfacial film is composed of alternating surface-active (SA) and co-surface-active (Co-SA) molecules, which allow the spontaneous formation of microemulsions by lowering the interfacial tension.

The oily phase can be formed especially from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from mixtures of said compounds. The oil phase may comprise triglycerides, including medium chain triglycerides, such as C8-C10 caprylic/capric triglycerides. In certain embodiments, the oil phase is present, inter alia, at a v/v concentration of about 2 to about 15%, about 7 to about 10%, or about 8 to about 9% of the microemulsion.

In certain embodiments, the aqueous phase includes, for example, water or glycol derivatives such as propylene glycol, glycol ethers, polyethylene glycol, or glycerol. Propylene glycol, diethylene glycol monoethyl ether and dipropylene glycol monoethyl ether are particularly preferred. Generally, the aqueous phase will comprise from about 1 to about 4% v/v of the microemulsion.

Surfactants for microemulsions include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, pegylated C8- _C10 glycerides or polyglyceryl- ₆ dioleate. In addition to these surfactants, co-surfactants also include short chain alcohols such as ethanol and propanol.

Certain compounds are the same for the three components discussed above, eg, aqueous phase, surfactant and co-surfactant. However, the skill level of the practitioner is sufficient to well use different compounds for each component of the same formulation.

In one embodiment, the ratio of co-surfactant to surfactant is from about 1/7 to about 1/2. In yet another embodiment, the concentration of surfactant in the microemulsion is from about 25 to about 75% v/v and the concentration of co-surfactant is from about 10 to about 55% v/v.

Similarly, co-solvents are also well known to those skilled in the art of formulation. In certain embodiments, co-solvents are those that facilitate drying and include, for example, absolute ethanol, isopropanol (2-propanol), or methanol.

For the chemical preparation of the products according to the invention, the person skilled in the art has inter alia recourse to "Chemical Abstracts" and the entire contents of the documents cited therein.

Depending on the identity and arrangement of the substituents, the active compounds may, if appropriate, exist in various stereoisomeric forms, especially as enantiomers and racemates. According to the invention it is possible to use both pure stereoisomers and mixtures thereof.

The subject matter of the present application is further described by the following non-limiting examples which further illustrate the invention and which are not intended and should not be construed as limiting the scope of the invention.

Example

Example 1: Stable fly repellent and parasiticidal efficacy in rats

This study evaluated the effectiveness of formulations of the invention containing fipronil and permethrin to repel and eradicate Stable flies (Stomoxys calcitrans) on rats after a single administration. On day 0, rats in a treatment group (group 2) were treated once with a topical formulation of the invention containing 9.2 (w/ w) Fipronil and 41.5% (w/w) permethrin, delivering a dose of 30 mg/kg permethrin and 6.7 mg/kg fipronil. Group 3 rats were treated with the formulation containing permethrin alone, delivering a dose of 30 mg/kg. The two treatment groups were compared to a control group treated with solvent system placebo.

Flies were exposed to treated rats for 1 hour and then removed. Dead flies were counted at the end of the exposure period and at 4 and 24 hours post-exposure. The fipronil + permethrin group exhibited very high levels of efficacy at all measured time points. Additionally, at the same dose level, the fipronil + permethrin group exhibited significantly higher repellence measured at 24 hours post-exposure compared to the permethrin-only group. This finding is significant because fipronil is not known to have repellent activity.

The diptericidal efficacy of the formulations is shown in Table 1 and presented in Figure 6. The repellency data are presented in Table 2 and presented in Figure 7.

Table 1.

EOE = end of exposure period

Table 2.

Example 2: Stable fly repellent and parasiticidal efficacy on dogs

This study evaluated the effectiveness of fipronil + permethrin in repelling and eradicating Stable flies (Stomoxyscalcitrans) in dogs after a single administration.

The fly-repellent and parasiticidal activity of the formulations according to the invention was evaluated on 10 dogs. Dogs were drawn-randomly assigned to one of two groups. Dogs in Group 1 were untreated: Dogs in Group 2 received a topical formulation of the invention containing the combination of fipronil and permethrin described in Table 3 below, administered once topically at a single point on Day 0, delivering approximately Doses of 6.70 mg fipronil/kg and 30.15 mg permethrin/kg.

Table 3: Formulations

On days 1, 14, 21 and 28, dogs were exposed to approximately 1003 to 7 day old stable flies. After approximately 60 minutes, live flies were aspirated into vials and dead flies were collected from cages. After all flies were collected, live flies were killed, counted (live and dead), and crushed to determine feeding status (fed vs. not fed). Fly exposure was not performed on day 7 due to improper eclosion of flies.

Fly repellence was based on a comparison of the number of feeding flies in the treatment group versus the control group during each exposure period. Repellence in treated dogs was 99% on day 1 and 85.9%, 84.6% and 61.7% on days 14, 21 and 28, respectively.

Parasiticidal efficacy was based on the number of live flies in the treatment group compared to the control group at the end of each exposure period. The parasiticidal efficacy in the treated dogs was 100% on day 1 and 98.7%, 95.5% and 81.3% on days 14, 21 and 28, respectively. The percent efficacy is listed in Table 3.

In this study, a composition comprising fipronil + permethrin provided > 84.6°/0 repellency and > 95.5% parasiticidal efficacy against stable flies (Stable flies) 3 weeks after treatment.

Summary data for the fipronil + permethrin compositions are shown in Table 4:

Table 4. Summary data

sky 1 7 14 twenty one 28 avoid 99.0 N/A 85.9 84.6 61.7

sky 1 7 14 twenty one 28 parasiticidal activity 100.0 N/A 98.7 95.5 81.3

Embodiment 3: the crystallization of active substance

Four experimental formulations were prepared with 6% w/w fipronil and 44.9% w/w permethrin and varying amounts of excipients N-dimethyldecylamide (DMDA) and diethylene glycol monoethyl ether (DGME). DMDA concentrations were varied between 5-20% w/w. These formulations were subjected to different low temperature conditions including -20°C, 4°C and 10°C; some samples were seeded with crystals grown from previous batches. Crystallization was observed for all formulations under various conditions.

DMDA-containing formulations of fipronil and permethrin as described herein were also subjected to low temperatures. Certain samples were seeded with crystals. Crystals were observed in the DMDA formulation.

Solvents were screened for compatibility with permethrin and ability to keep permethrin in solution. A summary of the tests and results is shown in Table 5.

table 5.

solvent the crystal Captex170 (caprylic/capric acid) 100% Oleic acid 100% Propylene Glycol immiscible Benzyl Benzoate less than 5% Propylene carbonate 100% Glyceryl cyclomethylene ether 100% ethanol 40% Isopropanol immiscible Diethylene glycol monoethyl ether (DGME) 100% N,N-Dimethyldecylamide (DMDA) less than 5%

Screening indicated that benzyl benzoate and N,N-dimethyldecylamide were the most compatible with permethrin in the experimental group.

In addition to screening the solvents for compatibility with permethrin, experimental batches were prepared, all containing 44.9% w/w permethrin and 6% w/w fipronil. Formulation results are shown in Tables 6 and 7.

Table 6.

Formulations containing N-methylpyrrolidone had the best physical stability in this group.

Table 7.

Note: 1) These results are approximate and based on laboratory screening data. 2) The amounts of DGME, DMDA, NMP are approximate and depend on the assay of actives. 3) All actives tested are assumed to be 100% in these experiments and calculations.

Example 4: A formulation of the invention fully described herein is shown in Table 8.

Table 8.

Example 5: Efficacy against fleas (Ctenocephalides felis) and ticks (Rhipicephalus sanguineus) on dogs.

A study was conducted to evaluate the effectiveness of three different formulations of the invention containing fipronil and permethrin in amounts delivering doses > 6.7 mg/kg and > 50.3 mg/kg, respectively, compared to those containing A formulation comparison of permethrin alone in a kg dose amount.

6 dogs each constituted 5 treatment groups. Group 1 dogs were untreated. Dogs in Groups 2, 3 and 4 on day 0 received a lick formulation of the invention containing 6.0% (w/w) fipronil and 44.9% (w/w) permethrin in different solvent systems. Dogs of group 5 were treated on day 0 with a paint formulation containing 44.9% (w/w) permethrin alone. The efficacy of each treatment relative to control group 1 was measured at each observation point. The formulation components are shown in Table 9 below.

Table 9

On days -1, 8, 15, 22 and 29, all dogs were infested with approximately 100 C. felis. Flea counts were performed on days 1, 9, 16, 23 and 30. All dogs were also infested with approximately 50 Rhipicephalus sanguineus on days -1, 14 and 28. Ticks were thumb counted on days 15 and 29 and counted and removed on days 1, 16 and 30.

Groups 2, 3 and 4 were similarly effective against fleas, ranging from 95-100% up to day 30. Group 5 efficacy was 51% on day 1 and peaked at 96% on day 9 before dropping to 13% on day 30.

At 24 hours after treatment, groups 2, 3, 4 and 5 were 69.1%, 89.9%, 94.7% and 70.2% effective against ticks, respectively. Efficacy against ticks ranged from 91-99% for all treatments at 24 hours post-infestation on day 15 and 56-81% on day 29. Efficacy against ticks for all treatments ranged from 96-100% at 48 hours post-infestation on day 16 and 74-85% on day 30.

This study demonstrates that formulations of the present invention provide superior efficacy against Ctenocephalides felis and Rhizocephalus sanguinosa compared to formulations containing permethrin alone. Efficacy data are also shown in Figures 4 and 5.

Example 6: Repellency and efficacy against Phlebotomus perniciosus on dogs

This study evaluated the effectiveness of two inventive formulations containing fipronil and permethrin in repelling and eradicating Phlebotomus perniciosus on dogs after a single administration.

Following a procedure very similar to that described in Example 2, the repellent and insecticidal efficacy of the formulations was studied. 5 dogs each constituted 3 treatment groups. Group 1 dogs were untreated. Dogs of Groups 2 and 3 were treated once on Day 0 with the formulation of the invention described in Table 10 below to deliver doses of > 6.7 mg/kg fipronil and > 50.3 mg/kg permethrin.

Table 10

On days 1, 7, 14, 21, 29, and 35, dogs were exposed to 80 (± 5) female P. pearflies. After 60 minutes, the sandflies were removed and classified as live (swollen or non-swollen), dead (swollen or non-swollen). Efficacy was determined by determining the number of deadflies approximately 4 hours after exposure and approximately 24 hours after exposure on days 2, 8, 15, 22 and 29. Repellence was measured by comparing the number of swollen flies (live or dead) in the treatment group to the number of swollen flies in the control group.

The repellence observed for dogs in Treatment Group 2 was measured to be 97.0%, 90.1%, 96.0%, 80.0%, 96.4% and 79.6% on days 1, 7, 14, 21, 29 and 35, respectively. The repellence observed for Group 3 dogs on days 1, 7, 14, 21, 29 and 35 was 94.4%, 94.7%, 99.3%, 88.6%, 97.3% and 82.5%, respectively.

The efficacy against Group 2 at 4 hours after exposure was 99.8%, 100.0%, 94.0%, 63.2%, 91.1% and 65.8% on days 1, 7, 14, 21, 29 and 35, respectively. The efficacy against Group 3 at 4 hours after exposure was 99.6%, 100.0%, 92.3%, 56.3%, 90.6% and 70.0% on days 1, 7, 14, 21, 29 and 35, respectively.

The efficacy against Group 2 at 24 hours after exposure was 100.0%, 99.4%, 94.4%, 66.3%, 91.7% and 69.6% on days 2, 8, 15, 22, 30 and 36, respectively. The efficacy against Group 3 at 4 hours after exposure was 99.6%, 100.0%, 92.6%, 58.0%, 93.1% and 70.7% on days 2, 8, 15, 22, 30 and 36, respectively.

This study demonstrates that the formulations of the invention provide excellent repellence of Phlebotomus perniciosus on dogs for at least 35 days and excellent insecticidal efficacy for at least 30 days after a single treatment. The data are also presented in Figure 3.

Example 7: Repellency and efficacy against stable flies (Stomoxys calcitrans) on dogs

This study was conducted to evaluate the repellency and efficacy of the inventive lotion formulations comprising the combination of fipronil and permethrin described in Table 8 above against Stable flies (Stomoxys calcitrans) after a single topical administration.

Following a procedure very similar to that of Example 2 above, 2 groups of 8 dogs each were formed. Dogs in Group 1 were untreated and served as a control group. Dogs in Group 2 were treated once on Day 0 with the formulation of Table 8, delivering a dose of 6.8 mg/kg fipronil and 50.5 mg/kg permethrin. On days 1, 7, 14, 21, 28 and 35, dogs were exposed to approximately 100 stable flies for approximately 60 minutes, after which the flies (live and dead) were collected and examined to determine feeding status. Repellence of the formulation administered to Group 2 dogs on days 1, 7, 14, 21, 28 and 35 was measured to be 100.0%, 100.0%, 99.2%, 97.3%, 96.6% and 88.7%, respectively. The insecticidal efficacy of the formulation applied to Group 2 dogs on days 1, 7, 14, 21, 28 and 35 was measured to be 100.0%, 99.9%, 99.4%, 99.6%, 98.3% and 98.3%, respectively. Repellency and efficacy data are presented in Figures 8 and 9.

For the formulation of Example 8, topical formulations containing permethrin at the dose levels administered had a very high level of repellency and insecticide against Stomoxys calcitrans with a duration of action of at least 35 days The potency is unexpected. For example, Fourie et al. reported that a topical formulation containing 10% imidacloprid and 50% permethrin (permethrin in the formulation at the same concentration as used in the examples of this application) prevented only 82% of stable stings 4 weeks after treatment. Flies fed on dogs and demonstrated an average efficacy of 85.6% over the 29 day evaluation period. (See "The Efficacy of a Topically Applied Combination of Imidacloprid and Permethrin Against Stomoxyscalcitrans on Dogs," Intern. J. Appl. Res. Vet. Med., 2006, vol. 4(1), pp. 29-33). In this study, the highest repellence observed throughout the 29-day evaluation period was 90.2% 1 day post-treatment, while all other time points were below 90%. The repellency and efficacy exhibited by the formulations of the present invention are surprisingly superior to other topical formulations comprising the same concentration of permethrin in combination with a different pesticidally active agent. The excellent repellency is particularly surprising since fipronil is not known to have any repellent activity.

Example 8: Repellence of mosquitoes (Culex pipiens) on dogs.

This study was conducted to evaluate the repellency and efficacy of the inventive lotion formulations described in Table 8 above against Culex pipiens after a single topical administration.

Following a procedure very similar to that described in Example 2, 2 groups of 8 dogs each were formed. Dogs in Group 1 were untreated and served as a control group. Group 2 dogs were treated once on Day 0 with the formulation of Table 8, delivering doses of 6.8 mg/kg fipronil and 50.5 mg/kg permethrin. Dogs were exposed to approximately 100 female Culex pipiens for approximately 60 minutes per dog on days 1, 7, 14, 21, and 28, after which mosquitoes (live and dead) were collected and examined to determine feeding state.

Repellence of the formulation administered to Group 2 dogs on days 1, 7, 14, 21 and 28 was measured to be 99.4%, 98.9%, 94.7%, 91.7% and 90.4%, respectively. The repellency data are shown in Figure 10.

Throughout this specification and claims, the words "comprises", "comprising" and "including" are used in a non-exclusive sense, unless the context requires otherwise.

As used herein, the term "about" when applied to a value is intended to encompass variations from the specified amount: in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5% in some embodiments, ±1% in some embodiments, ±0.5% in some embodiments, and ±0.1% in some embodiments, these variations are suitable for practicing the disclosed method or use disclosed composition.

All publications, patent applications, patents, and other references are herein incorporated by reference to the same extent as if each individual publication, patent application, patent, and other reference was specifically and individually indicated to be incorporated by reference. It should be understood that, although numerous patent applications, patents, and other references are mentioned herein, it is not an admission that any of these documents form part of the common general knowledge in the art.

While the foregoing subject matter has been described in detail by way of example and embodiment for purposes of clarity of understanding, those skilled in the art will recognize that certain changes and modifications will come within the scope of the appended claims.

While certain embodiments of the invention have been described in detail above, it should be understood that the invention defined in the preceding paragraphs is not limited to the specific details of the foregoing description, since many obvious variations are possible without departing from the spirit or spirit of the invention. scope.

Claims (25)

1. it is used to processing and preventing the topical composition that ectoparasite infects, comprising：

2% (w/w) to 15% (w/w) ethiprole；

30% (w/w) to 55% (w/w) Permethrin；With

One or more neutral oil and N-Methyl pyrrolidone, wherein the neutral oil is C₈-C₁₀The triglyceride of fatty acid, it is pungent Acid and the ester of capric acid fatty acid and Propylene Glycol, C₈-C₁₀Fatty acid and linoleic triglyceride in combination, C₈-C₁₀Fat The triglyceride of sour and in combination succinic acid, C₈-C₁₀The propylene glycol diesters of fatty acid and succinic acid in combination, or its Mixture, wherein one or more neutral oil and N-Methyl pyrrolidone are with 1:2.0 to 1:One or more of 3.5 is neutral Oil:The weight of N-Methyl pyrrolidone:Weight is than existing.

2. compositionss of claim 1, wherein the ethiprole exists with the concentration of 4% (w/w) to 8% (w/w).

3. compositionss of claim 1, wherein the ethiprole exists with the concentration of 6% (w/w).

4. compositionss of claim 1, wherein the Permethrin exists with the concentration of 35% (w/w) to 50% (w/w).

5. compositionss of claim 1, wherein the Permethrin exists with the concentration of 40% (w/w) to 48% (w/w).

6. compositionss of claim 1, wherein the Permethrin exists with the concentration of 45% (w/w).

7. compositionss of claim 1, wherein the ethiprole so that the concentration of 6.0% (w/w) is present the Permethrin with The concentration of 45% (w/w) is present.

8. compositionss of claim 1, wherein one or more neutral oil and the N-Methyl pyrrolidone are with 1:2.0 extremely 1:3.0 one or more neutral oil:The weight of N-Methyl pyrrolidone:Weight is than existing.

9. compositionss of claim 1, wherein one or more neutral oil is with the concentration of 12% (w/w) to 14% (w/w) Exist and the N-Methyl pyrrolidone exists with the concentration of 35% (w/w).

10. compositionss of claim 1, wherein one or more neutral oil and the N-Methyl pyrrolidone are with 1:2.5 To 1:3.0 one or more neutral oil:The weight of N-Methyl pyrrolidone:Weight is than existing.

The compositionss of 11. claim 1, wherein one or more neutral oil and the N-Methyl pyrrolidone are with 1:2.5 To 1:3.5 one or more neutral oil:The weight of N-Methyl pyrrolidone:Weight is than existing.

The compositionss of 12. claim 1, wherein one or more neutral oil and the N-Methyl pyrrolidone are with 1: 2.2 to 1:2.4 one or more neutral oil:The weight of N-Methyl pyrrolidone:Weight ratio is deposited.

The compositionss of 13. claim 1, wherein one or more neutral oil and the N-Methyl pyrrolidone are with 1:2.5 To 1:2.8 one or more neutral oil:The weight of N-Methyl pyrrolidone:Weight is than existing.

The compositionss of 14. claim 1, wherein one or more neutral oil is with C₈And C₁₀Chain length classification plant The triglyceride of fatty acid.

The compositionss of 15. claim 1, comprising

6% (w/w) ethiprole；

45% (w/w) Permethrin；

12% to 14% (w/w) with C₈And C₁₀Chain length classification vegetable fatty acid triglyceride (w/w)；

35% (w/w) N-Methyl pyrrolidone；With

The butylated hydroxy-methylbenzenes of 0.1% (w/w).

The compositionss of 16. claim 1, also comprising antioxidant.

The compositionss of 17. claim 16, wherein the antioxidant is butylated hydroxy-methylbenzene.

The compositionss of any one of 18. claim 1 to 17, also comprising one or more additional active agent.

The compositionss of 19. claim 18, wherein one or more additional active agent is avilamycin, it is close than mycin, it is many Killing teichomycin, class multiple killing teichomycin, benzimidazole, levamisole, pyrantel, morantel, praziquantel, closantel, clorsulon, ammonia Base acetonitrile activating agent, insect growth regulator, IGR, anabasine or aryl and pyrroles's -2- base cyano ethyl amino activating agents, or its Combination.

20. liniment compositionss, comprising

2% (w/w) to 15% (w/w) ethiprole；

30% (w/w) to 55% (w/w) Permethrin；With

One or more neutral oil and N-Methyl pyrrolidone, wherein the neutral oil is C₈-C₁₀The triglyceride of fatty acid, it is pungent Acid and the ester of capric acid fatty acid and Propylene Glycol, C₈-C₁₀Fatty acid and linoleic triglyceride in combination, C₈-C₁₀Fat The triglyceride of sour and in combination succinic acid, C₈-C₁₀The propylene glycol diesters of fatty acid and succinic acid in combination, or its Mixture, wherein one or more neutral oil and N-Methyl pyrrolidone are with 1:2.5 to 1:3.5 weight:Weight ratio is deposited ,

Wherein described compositionss are the liquid with 1mL to 10mL volumes.

The compositionss of 21. claim 1 or 20, also comprising the relative ethiprole peak face that 3 months are measured by HPLC after preparation Ethiprole sulfone of the product less than 3.5% area.

The compositionss of 22. claim 1 or 20, also comprising ethiprole sulfone, wherein after preparation 3 months ethiprole sulfones the amount Do not increase 50% of the primary quantity more than the ethiprole sulfone existed when preparing.

A kind of 23. compositionss, comprising

2% (w/w) to 15% (w/w) ethiprole；

30% (w/w) to 55% (w/w) Permethrin；

One or more neutral oil and N-Methyl pyrrolidone；

With ethiprole sulfone, wherein the neutral oil is C₈-C₁₀The triglyceride of fatty acid, octanoic acid and capric acid fatty acid and Propylene Glycol Ester, C₈-C₁₀Fatty acid and linoleic triglyceride in combination, C₈-C₁₀Fatty acid and succinic acid in combination Triglyceride, C₈-C₁₀The propylene glycol diesters of fatty acid and succinic acid in combination, or its mixture, wherein it is described a kind of or Various neutral oils are with a certain amount of presence, wherein the amount in 3 months ethiprole sulfones after preparation does not increase more than when preparing The 50% of the primary quantity of the ethiprole sulfone for existing.

Purposes of the combination of 24. ethiproles and Permethrin and NMP and one or more neutral oil in medicine is prepared, the medicine Thing is used to processing and preventing the parasitic infestations in animal, wherein the neutral oil is selected from C₈-C₁₀The triglyceride of fatty acid, it is pungent Acid and the ester of capric acid fatty acid and Propylene Glycol, C₈-C₁₀Fatty acid and linoleic triglyceride in combination, C₈-C₁₀Fat The triglyceride of sour and in combination succinic acid, C₈-C₁₀The propylene glycol diesters of fatty acid and succinic acid in combination, or its Mixture.

Purposes of the compositionss of 25. claim 1 in medicine is prepared, the medicine is used to processing and preventing the parasitism in animal The purposes that thing infects.